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  • 1. Abdallah, Qasem M. A.
    et al.
    Phillips, Roger M.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cosentino, Laura
    Abdel-Rahman, Hamdy
    Etzad, Jasarat
    Wheelhouse, Richard T.
    Kiakos, Konstantinos
    Bingham, John P.
    Hartley, John A.
    Patterson, Laurence H.
    Pors, Klaus
    Minor structural modifications to alchemix influence mechanism of action and pharmacological activity2012In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 83, no 11, p. 1514-1522Article in journal (Refereed)
    Abstract [en]

    Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

  • 2. Al-Minawi, Ali Z.
    et al.
    Lee, Yin-Fai
    Håkansson, Daniel
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lundin, Cecilia
    Saleh-Gohari, Nasrollah
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bryant, Helen E.
    Meuth, Mark
    Hinz, John M.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The ERCC1/XPF endonuclease is required for completion of homologous recombination at DNA replication forks stalled by inter-strand cross-links2009In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 19, p. 6400-6413Article in journal (Refereed)
    Abstract [en]

    Both the ERCC1-XPF complex and the proteins involved in homoIogous recombination (HR) have critical roles in inter-strand cross-link (ICL) repair. Here, we report that mitomycin C-induced lesions inhibit replication fork elongation. Furthermore, mitomycin C-induced DNA double-strand breaks (DSBs) are the result of the collapse of ICL-stalled replication forks. These are not formed through replication run off, as we show that mitomycin C or cisplatin-induced DNA lesions are not incised by global genome nucleotide excision repair (GGR). We also suggest that ICL-lesion repair is initiated either by replication or transcription, as the GGR does not incise ICL-lesions. Furthermore, we report that RAD51 foci are induced by cisplatin or mitomycin C independently of ERCC1, but that mitomycin C-induced HR measured in a reporter construct is impaired in ERCC1-defective cells. These data suggest that ERCC1-XPF plays a role in completion of HR in ICL repair. We also find no additional sensitivity to cisplatin by siRNA co-depletion of XRCC3 and ERCC1, showing that the two proteins act on the same pathway to promote survival.

  • 3. Al-Minawi, Ali Z
    et al.
    Saleh-Gohari, Nasrollah
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The ERCC1/XPF endonuclease is required for efficient single-strand annealing and gene conversion in mammalian cells.2007In: Nucleic Acids Res, ISSN 1362-4962Article in journal (Refereed)
  • 4.
    Al-Minawi, Ali Z
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Saleh-Gohari, Nasrollah
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The ERCC1/XPF endonuclease is required for efficient single-strand annealing and gene conversion in mammalian cells2008In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 36, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The mammalian ERCC1-XPF endonuclease has a suggested role in the repair of DNA double-strand breaks (DSB) by single-strand annealing (SSA). Here, we investigated the role of ERCC1 in homologous recombination in mammalian cells, and confirm a role of ERCC1 in SSA. Interestingly, we also report an unexpected role for ERCC1 in gene conversion. This provides support that gene conversion in mammalian somatic cells is carried out through synthesis-dependent strand annealing, rather than through a double Holliday Junction mechanism. Moreover, we find low frequencies of SSA and gene conversion in G1-arrested cells, suggesting that SSA is not a frequent DSB repair pathway in G1-arrested mammalian cells, even in the presence of perfect repeats. Furthermore, we find that SSA is not influenced by inhibition of CDK2 (using Roscovitine), ATM (using Caffeine and KU55933), Chk1 (using CEP-3891) or DNA-PK (using NU7026).

  • 5.
    Al-Ubaidi, Firas L. T.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Egevad, Lars
    Granfors, Torvald
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    CASTRATION THERAPY OF PROSTATE CANCER RESULTS IN DOWNREGULATION OF HIF-1 alpha LEVELS2012In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 82, no 3, p. 1243-1248Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: Neoadjuvant androgen deprivation in combination with radiotherapy of prostate cancer is used to improve radioresponsiveness and local tumor control. Currently, the underlying mechanism is not well understood. Because hypoxia causes resistance to radiotherapy, we wanted to test whether castration affects the degree of hypoxia in prostate cancer. Methods and Materials: In 14 patients with locally advanced prostate cancer, six to 12 prostatic needle core biopsy specimens were taken prior to castration therapy. Bilateral orchidectomy was performed in 7 patients, and 7 were treated with a GnRH-agonist (leuprorelin). After castrationm two to four prostatic core biopsy specimens were taken, and the level of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in cancer was determined by immunofluorescence. Results: Among biopsy specimens taken before castration, strong HIF-1 alpha expression (mean intensity above 30) was shown in 5 patients, weak expression (mean intensity 10-30) in 3 patients, and background levels of HIF-1 alpha (mean intensity 0-10) in 6 patients. Downregulation of HIF-1 alpha expression after castration was observed in all 5 patients with strong HIF-1 alpha precastration expression. HIF-1 alpha expression was also reduced in 2 of 3 patients with weak HIF-1 alpha precastration expression. Conclusions: Our data suggest that neoadjuvant castration decreases tumor cell hypoxia in prostate cancer, which may explain increased radiosensitivity after castration.

  • 6. Arnaudeau, C
    et al.
    Helleday, T
    Stockholm University.
    Jenssen, D
    Stockholm University.
    The RAD51 protein supports homologous recombination by an exchange mechanism in mammalian cells.1999In: J Mol Biol, ISSN 0022-2836, Vol. 289, no 5, p. 1231-8Article in journal (Refereed)
  • 7. Arnaudeau, C
    et al.
    Lundin, C
    Stockholm University.
    Helleday, T
    Stockholm University.
    DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells.2001In: J Mol Biol, ISSN 0022-2836, Vol. 307, no 5, p. 1235-45Article in journal (Refereed)
  • 8. Arnaudeau, C
    et al.
    Rozier, L
    Cazaux, C
    Defais, M
    Jenssen, D
    Stockholm University.
    Helleday, T
    Stockholm University.
    RAD51 supports spontaneous non-homologous recombination in mammalian cells, but not the corresponding process induced by topoisomerase inhibitors.2001In: Nucleic Acids Res, ISSN 1362-4962, Vol. 29, no 3, p. 662-7Article in journal (Refereed)
  • 9. Arnaudeau, C
    et al.
    Tenorio Miranda, E
    Jenssen, D
    Stockholm University.
    Helleday, T
    Stockholm University.
    Inhibition of DNA synthesis is a potent mechanism by which cytostatic drugs induce homologous recombination in mammalian cells.2000In: Mutat Res, ISSN 0027-5107, Vol. 461, no 3, p. 221-8Article in journal (Refereed)
  • 10.
    Arnaudeau, Catherine
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lundin, Cecilia
    Stockholm University, Faculty of Social Sciences, Department of Applied Communications Science - GI and IHR.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    DNA Double-strand Breaks Associated with Replication Forks are Predominantly Repaired by Homologous Recombination Involving an Exchange Mechanism in Mammalian Cells2001In: Journal of Molecular Biology, ISSN 0022-2836, Vol. 307, no 5, p. 1235-45Article in journal (Refereed)
    Abstract [en]

    DNA double-strand breaks (DSB) represent a major disruption in the integrity of the genome. DSB can be generated when a replication fork encounters a DNA lesion. Recombinational repair is known to resolve such replication fork-associated DSB, but the molecular mechanism of this repair process is poorly understood in mammalian cells. In the present study, we investigated the molecular mechanism by which recombination resolves camptothecin (CPT)-induced DSB at DNA replication forks. The frequency of homologous recombination (HR) was measured using V79/SPD8 cells which contain a duplication in the endogenous hprt gene that is resolved by HR. We demonstrate that DSB associated with replication forks induce HR at the hprt gene in early S phase. Further analysis revealed that these HR events involve an exchange mechanism. Both the irs1SF and V3-3 cell lines, which are deficient in HR and non-homologous end joining (NHEJ), respectively, were found to be more sensitive than wild-type cells to DSB associated with replication forks. The irs1SF cell line was more sensitive in this respect than V3-3 cells, an observation consistent with the hypothesis that DSB associated with replication forks are repaired primarily by HR. The frequency of formation of DSB associated with replication forks was not affected in HR and NHEJ deficient cells, indicating that the loss of repair, rather than the formation of DSB associated with replication forks is responsible for the increased sensitivity of the mutant strains. We propose that the presence of DSB associated with replication forks rapidly induces HR via an exchange mechanism and that HR plays a more prominent role in the repair of such DSB than does NHEJ

  • 11. Bartkova, Jirina
    et al.
    Rezaei, Nousin
    Liontos, Michalis
    Karakaidos, Panagiotis
    Kletsas, Dimitris
    Issaeva, Natalia
    Stockholm University.
    Vassiliou, Leandros-Vassilios F
    Kolettas, Evangelos
    Niforou, Katerina
    Zoumpourlis, Vassilis C
    Takaoka, Munenori
    Nakagawa, Hiroshi
    Tort, Frederic
    Fugger, Kasper
    Johansson, Fredrik
    Stockholm University.
    Sehested, Maxwell
    Andersen, Claus L
    Dyrskjot, Lars
    Ørntoft, Torben
    Lukas, Jiri
    Kittas, Christos
    Helleday, Thomas
    Stockholm University.
    Halazonetis, Thanos D
    Bartek, Jiri
    Gorgoulis, Vassilis G
    Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.2006In: Nature, ISSN 1476-4687, Vol. 444, no 7119, p. 633-7Article in journal (Refereed)
  • 12. Bauerschmidt, Christina
    et al.
    Woodcock, Michael
    Stevens, David L.
    Hill, Mark A.
    Rothkamm, Kai
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cells2011In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 317, no 3, p. 330-337Article in journal (Refereed)
    Abstract [en]

    Cohesin, a hetero-tetrameric complex of SMC1, SMC3, Rad21 and Scc3, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. Following DNA damage, cohesin accumulates at and promotes the repair of DNA double-strand breaks. In addition, phosphorylation of the SMC1/3 subunits contributes to DNA damage-induced cell cycle checkpoint regulation. The aim of this study was to determine the regulation and consequences of SMC1/3 phosphorylation as part of the cohesin complex. We show here that the ATM-dependent phosphorylation of SMC1 and SMC3 is mediated by H2AX, 53BP1 and MDC1. Depletion of RAD21 abolishes these phosphorylations, indicating that only the fully assembled complex is phosphorylated. Comparison of wild type SMC1 and SMC1S966A in fluorescence recovery after photo-bleaching experiments shows that phosphorylation of SMC1 is required for an increased mobility after DNA damage in G2-phase cells, suggesting that ATM-dependent phosphorylation facilitates mobilization of the cohesin complex after DNA damage.

  • 13. Bavoux, Clarisse
    et al.
    Leopoldino, Andréia Machado
    Bergoglio, Valérie
    O-Wang, Jiyang
    Ogi, Tomoo
    Bieth, Anne
    Judde, Jean-Gabriel
    Pena, Sérgio Danilo Junho
    Poupon, Marie-France
    Helleday, Thomas
    Stockholm University.
    Tagawa, Masatoshi
    Machado, Carlosrenato
    Hoffmann, Jean-Sébastien
    Cazaux, Christophe
    Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis.2005In: Cancer Res, ISSN 0008-5472, Vol. 65, no 1, p. 325-30Article in journal (Refereed)
  • 14. Beck, Halfdan
    et al.
    Nahse, Viola
    Larsen, Marie Sofie Yoo
    Groth, Petra
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Clancy, Trevor
    Lees, Michael
    Jörgensen, Mette
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Syljuasen, Randi G.
    Sörensen, Claus Storgaard
    Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase2010In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 188, no 5, p. 629-638Article in journal (Refereed)
    Abstract [en]

    Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.

  • 15. Blundred, Rachel
    et al.
    Myers, Katie
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Goldman, Alastair S H
    Bryant, Helen E
    Human RECQL5 overcomes thymidine-induced replication stress.2010In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 9, no 9, p. 964-75Article in journal (Refereed)
    Abstract [en]

    Accurate DNA replication is essential to genome integrity and is controlled by five human RecQ helicases, of which at least three prevent cancer and ageing. Here, we have studied the role of RECQL5, which is the least characterised of the five human RecQ helicases. We demonstrate that overexpressed RECQL5 promotes survival during thymidine-induced slowing of replication forks in human cells. The RECQL5 protein relocates specifically to stalled replication forks and suppresses thymidine-induced RPA foci, CHK1 signalling, homologous recombination and gammaH2AX activation. It is unlikely that RECQL5 promotes survival through translesion synthesis as PCNA ubiquitylation is also reduced. Interestingly, we also found that overexpressing RECQL5 relieves cells of the cell cycle arrest normally imposed by thymidine, but without causing mutations. In conclusion, we propose that RECQL5 stabilises the replication fork allowing replication to overcome the effects of thymidine and complete the cell cycle.

  • 16. Bolderson, Emma
    et al.
    Scorah, Jennifer
    Helleday, Thomas
    Stockholm University.
    Smythe, Carl
    Meuth, Mark
    ATM is required for the cellular response to thymidine induced replication fork stress.2004In: Hum Mol Genet, ISSN 0964-6906, Vol. 13, no 23, p. 2937-45Article in journal (Refereed)
  • 17. Bryant, H E
    et al.
    Helleday, T
    Stockholm University.
    Poly(ADP-ribose) polymerase inhibitors as potential chemotherapeutic agents.2004In: Biochem Soc Trans, ISSN 0300-5127, Vol. 32, no Pt 6, p. 959-61Article, review/survey (Other (popular science, discussion, etc.))
  • 18. Bryant, Helen E
    et al.
    Helleday, Thomas
    Stockholm University.
    Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair.2006In: Nucleic Acids Res, ISSN 1362-4962, Vol. 34, no 6, p. 1685-91Article in journal (Refereed)
  • 19. Bryant, Helen E
    et al.
    Petermann, Eva
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jemth, Ann-Sofie
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Loseva, Olga
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Issaeva, Natalia
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Fernandez, Serena
    McGlynn, Peter
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination.2009In: The EMBO journal, ISSN 1460-2075, Vol. 28, no 17, p. 2601-15Article in journal (Refereed)
    Abstract [en]

    If replication forks are perturbed, a multifaceted response including several DNA repair and cell cycle checkpoint pathways is activated to ensure faithful DNA replication. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1) binds to and is activated by stalled replication forks that contain small gaps. PARP1 collaborates with Mre11 to promote replication fork restart after release from replication blocks, most likely by recruiting Mre11 to the replication fork to promote resection of DNA. Both PARP1 and PARP2 are required for hydroxyurea-induced homologous recombination to promote cell survival after replication blocks. Together, our data suggest that PARP1 and PARP2 detect disrupted replication forks and attract Mre11 for end processing that is required for subsequent recombination repair and restart of replication forks.

  • 20. Bryant, Helen E
    et al.
    Schultz, Niklas
    Stockholm University.
    Thomas, Huw D
    Parker, Kayan M
    Flower, Dan
    Lopez, Elena
    Kyle, Suzanne
    Meuth, Mark
    Curtin, Nicola J
    Helleday, Thomas
    Stockholm University.
    Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.2005In: Nature, ISSN 1476-4687, Vol. 434, no 7035, p. 913-7Article in journal (Refereed)
  • 21. Bryant, Helen E
    et al.
    Ying, Songmin
    Helleday, Thomas
    Stockholm University.
    Homologous recombination is involved in repair of chromium-induced DNA damage in mammalian cells.2006In: Mutat Res, ISSN 0027-5107, Vol. 599, no 1-2, p. 116-23Article in journal (Refereed)
  • 22. Chan, Norman
    et al.
    Pires, Isabel M
    Bencokova, Zuzana
    Coackley, Carla
    Luoto, Kaisa R
    Bhogal, Nirmal
    Lakshman, Minalini
    Gottipati, Ponnari
    Oliver, F Javier
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hammond, Ester M
    Bristow, Robert G
    Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment.2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 20, p. 8045-54Article in journal (Refereed)
    Abstract [en]

    Acute and chronic hypoxia exists within the three-dimensional microenvironment of solid tumors and drives therapy resistance, genetic instability, and metastasis. Replicating cells exposed to either severe acute hypoxia (16 hours with 0.02% O(2)) followed by reoxygenation or moderate chronic hypoxia (72 hours with 0.2% O(2)) treatments have decreased homologous recombination (HR) protein expression and function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition itself did not affect HR expression or function, we observed increased clonogenic killing in HR-deficient hypoxic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 overexpression. PARP1(-/-) murine embryonic fibroblasts (MEF) showed a proliferative disadvantage under hypoxic gassing when compared with PARP1(+/+) MEFs. PARP-inhibited hypoxic cells accumulated γH2AX and 53BP1 foci as a consequence of altered DNA replication firing during S phase-specific cell killing. In support of this proposed mode of action, PARP inhibitor-treated xenografts displayed increased γH2AX and cleaved caspase-3 expression in RAD51-deficient hypoxic subregions in vivo, which was associated with decreased ex vivo clonogenic survival following experimental radiotherapy. This is the first report of selective cell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated "contextual synthetic lethality." As all solid tumors contain aggressive hypoxic cells, this may broaden the clinical utility of PARP and DNA repair inhibition, either alone or in combination with radiotherapy and chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations.

  • 23.
    Chatzakos, Vicky
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Slätis, Katharina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Djureinovic, Tatjana
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hunt, Mary C.
    N-Acyl Taurines are Anti-Proliferative in Prostate Cancer Cells2012In: Lipids, ISSN 0024-4201, E-ISSN 1558-9307, Vol. 47, no 4, p. 355-361Article in journal (Refereed)
    Abstract [en]

    Endocannabinoids have been implicated in cancer development and cause heterogenous effects in tumor cells, by inducing apoptosis, reducing migration, causing anti-angiogenic activity and alterations in the cell cycle resulting in growth arrest. Recently, several novel amides of fatty acids that are structurally related to endocannabinoids have been isolated from mammalian sources, although the functions of these fatty amides are not well studied. One group of these novel fatty acid amides are the N-acyl taurines (fatty acids conjugated to the amino acid taurine). This study examined if N-acyl taurines, specifically N-arachidonoyl taurine and N-oleoyl taurine could function in a similar way to endocannabinoids and result in cell cycle alterations or growth arrest in the human prostate adenocarcinoma cell line PC-3. PC-3 cells were treated with various concentrations of N-arachidonoyl taurine and N-oleoyl taurine and cell proliferation and viability was measured using resazurin and colony formation assays. Effects of N-acyl taurines on the cell cycle was measured using FACS analysis. Treatment with N-arachidonoyl taurine and N-oleoyl taurine resulted in a significant reduction in proliferation of PC-3 cells, even at concentrations as low as 1 mu M. Treatment with N-oleoyl taurine resulted in an increased number of cells in the subG1 population, suggesting apoptosis, and a lower number of cells in S-phase of the cell cycle. In summary, our results show that novel biologically active lipids, the N-acyl taurines, result in reduced proliferation in PC-3 cells.

  • 24. Cheng, Wen-Hsing
    et al.
    Muftic, Diana
    Muftuoglu, Meltem
    Dawut, Lale
    Morris, Christa
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Shiloh, Yosef
    Bohr, Vilhelm A
    WRN is required for ATM activation and the S-phase checkpoint in response to interstrand cross-link-induced DNA double-strand breaks.2008In: Mol Biol Cell, ISSN 1939-4586, Vol. 19, no 9, p. 3923-33Article in journal (Refereed)
  • 25. Duro, Eris
    et al.
    Lundin, Cecilia
    Ask, Katrine
    Sanchez-Pulido, Luis
    MacArtney, Thomas J.
    Toth, Rachel
    Ponting, Chris P.
    Groth, Anja
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rouse, John
    Identification of the MMS22L-TONSL Complex that Promotes Homologous Recombination2010In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 40, no 4, p. 632-644Article in journal (Refereed)
    Abstract [en]

    Budding yeast Mms22 is required for homologous recombination (HR)-mediated repair of stalled or broken DNA replication forks. Here we identify a human Mms22-like protein (MMS22L) and an MMS22L-interacting protein, NF kappa BIL2/TONSL. Depletion of MMS22L or TONSL from human cells causes a high level of double-strand breaks (DSBs) during DNA replication. Both proteins accumulate at stressed replication forks, and depletion of MMS22L or TONSL from cells causes hypersensitivity to agents that cause S phase-associated DSBs, such as topoisomerase (TOP) inhibitors. In this light, MMS22L and TONSL are required for the HR-mediated repair of replication fork-associated DSBs. In cells depleted of either protein, DSBs induced by the TOP1 inhibitor camptothecin are resected normally, but the loading of the RAD51 recombinase is defective. Therefore, MMS22L and TONSL are required for the maintenance of genome stability when unscheduled DSBs occur in the vicinity of DNA replication forks.

  • 26. El-Khamisy, Sherif F
    et al.
    Saifi, Gulam M
    Weinfeld, Michael
    Johansson, Fredrik
    Stockholm University.
    Helleday, Thomas
    Stockholm University.
    Lupski, James R
    Caldecott, Keith W
    Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.2005In: Nature, ISSN 1476-4687, Vol. 434, no 7029, p. 108-13Article in journal (Refereed)
  • 27.
    Elvers, Ingegerd
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Deperas-Kaminska, Marta
    Joint Institute for Nuclear Research, Dubna, Russia.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    UV-induced replication fork collapse in DNA polymerase η deficient cells is independent of the MUS81 endonucleaseManuscript (preprint) (Other academic)
    Abstract [en]

    The MUS81 endonuclease was initially identified in resonse to UV and MMS lesions, and has been implicated in replication fork collapse after exposure to cross-linking agents. After stalling of replication forks by hydroxyurea treatment, the forks collapse independently of MUS81 but the endonuclease is required for replication fork restart. However in cells deficient in the Werner helicase, MUS81 is needed for collapse of replication forks after hydroxyurea treatment, indicating that the endonuclease might play a role in replication fork collapse in cells with impaired replication. UV irradiation induces DNA damage that physically block replication fork elongation but may be bypassed by translesion synthesis polymerases. Here we have investigated the role of MUS81 after UV irradiation of human fibroblasts deficient in Polη, and restored (wild-type) cells. We show that in wild-type cells, depletion of MUS81 does not affect survival after UV irradiation. However in Polη deficient cells, MUS81 depletion further lowers the survival after exposure to UV. In spite of this, replication forks collapse in UV irradiated Polη deficient cells independently of MUS81.

  • 28.
    Elvers, Ingegerd
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Djureinovic, Tatjana
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lagerqvist, Anne
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Stoimenov, Ivaylo
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    CHK1 activity is required for replication fork elongation but not stabilisation after UV irradiationArticle in journal (Refereed)
    Abstract [en]

    UV-induced DNA damage cause an efficient block for elongating replication forks. Since CHK1 has been shown to stabilise replication forks following hydroxyurea treatment, we wanted to test if the increased killing with the unspecific kinase inhibitor caffeine, inhibiting ATM and ATR amongst other kinases, is explained by inability to activate the CHK1 kinase to stabilise UV-stalled replication forks. For this, we used cells deficient in Polη, a translesion synthesis polymerase capable of properly bypassing the UV-induced cis-syn TT pyrimidine dimer, which blocks replication. These cells, derived from the variant type of xeroderma pigmentosum, are sensitised to UV irradiation by caffeine treatment. We demonstrate that both caffeine and CHK1 inhibition, using CEP-3891, equally retards replication fork elongation after UV treatment in Polη deficient cells. Interestingly, we found more pronounced UV-sensitisation by caffeine than with the CHK1 inhibitor in clonogenic survival experiments. Furthermore, we demonstrate an increased collapse of UV-stalled forks after caffeine treatment, but not after CHK1 inhibition, demonstrating that CHK1 activity is not required for stabilisation of UV-stalled replication forks. These data suggest that stabilisation and elongation at UV-stalled forks are distinct mechanisms, and that CHK1 is only involved in fork elongation. 

  • 29.
    Elvers, Ingegerd
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Djureinovic, Tatjana
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Lagerqvist, Anne
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Stoimenov, Ivaylo
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    UVC–stalled replication forks readily collapse into DNA double-strand breaksin the absence of DNA polymerase η and independently of Mus81 in humancellsManuscript (preprint) (Other academic)
  • 30.
    Elvers, Ingegerd
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Groth, Petra
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    UV stalled replication forks restart by re-priming in human fibroblasts2011In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 16, p. 7049-7057Article in journal (Refereed)
    Abstract [en]

    Restarting stalled replication forks is vital to avoid fatal replication errors. Previously, it was demonstrated that hydroxyurea-stalled replication forks use an active restart mechanism or rescue replication by new origin firing. Using the DNA fiber assay, we find to our surprise no evidence that UV-damaged replication forks are arrested and only detect a slightly reduced fork speed on a UV-damaged template. Interestingly, no evidence for UV-induced fork stalling was observed even in translesion synthesis defective, Polηmut cells. In contrast, using an assay to measure DNA molecule elongation at the fork, we observe that DNA elongation is severely blocked, particularly in UV-damaged Polηmut cells. In conclusion, these data suggest that UV-blocked replication forks restart effectively through re-priming. If left unfilled, the gap behind a re-primed fork may collapse into a DNA double-strand break that is repaired by a recombination pathway, similar to the fate of replication forks collapsed after hydroxyurea treatment.

  • 31. Evers, Bastiaan
    et al.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jonkers, Jos
    Targeting homologous recombination repair defects in cancer2010In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 31, no 8, p. 372-380Article, review/survey (Refereed)
    Abstract [en]

    DNA repair is essential for cells to maintain genome stability in an environment that constantly produces DNA damage. There is a growing appreciation that defects in homologous recombination repair underlie hereditary and sporadic tumourigenesis, and that deficiency in this pathway may dictate the sensitivity of tumours to certain DNA-damaging agents. Homologous recombination deficiency (HRD) may therefore prove to be a diagnostic criterion per se if appropriate biomarkers become available to identify these tumours. In addition, homologous recombination-deficient tumours are more sensitive to inhibition of other DNA repair pathways through so-called 'synthetic lethal interactions', a principle that is currently being tested in clinical trials. Finally, homologous recombination repair-deficient cells may have an increased dependency on certain cell-cycle checkpoints, which can be therapeutically exploited. Here we describe recent advances in strategies to identify and target HRD tumours, approaches to overcome resistance, and combinatory strategies to optimize treatment outcome.

  • 32.
    Frumerie, Clara
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sylwan, Lina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Yu, Anna
    Department of Clinical Chemistry, Danderyd Hospital and Karolinska Institute, Stockholm, Sweden.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bacteriophage P2 integrase: another possible tool for site-specific recombination in eukaryotic cells2008In: Journal of Applied Microbiology, ISSN 1364-5072, E-ISSN 1365-2672, Vol. 105, no 1, p. 290-299Article in journal (Refereed)
    Abstract [en]

    AIMS: To investigate if the site-specific tyrosine integrase (Int) from phage P2 has features that would make it interesting for use of gene transfer into eukaryotic cells. These include the possibility of promoting recombination with a nonphage sequence, abolishing the requirement for the bacterial DNA-binding and -bending protein integration host factor (IHF), and localization to the nucleus of eukaryotic cells. METHODS AND RESULTS: We show that the Int protein catalyzes site-specific recombination using a human sequence in Escherichia coli and in vitro although not as efficiently as with the wild-type bacterial sequence, and that insertion of high mobility group recognition boxes in the phage attachment site substrate abolish the requirement of IHF and allows efficient recombination in vitro in a eukaryotic cell extract. Furthermore, we show by fluorescence that the Int protein contains a functional intrinsic nuclear localization signal, localizing it to the nucleus in both HeLa and 293 cells. CONCLUSIONS: We conclude that P2 Int may be a potential tool for site-specific integration of genes into the human chromosome. SIGNIFICANCE AND IMPACT OF THE STUDY: The study implies the possibility of using multiple prokaryotic Int proteins with different specific integration sites in human cells for future gene therapy programmes.

  • 33. Gottipati, Ponnari
    et al.
    Cassel, Tobias N.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Savolainen, Linda
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription-associated recombination is dependent on replication in Mammalian cells2008In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 28, no 1, p. 154-64Article in journal (Refereed)
    Abstract [en]

    Transcription can enhance recombination; this is a ubiquitous phenomenon from prokaryotes to higher eukaryotes. However, the mechanism of transcription-associated recombination in mammalian cells is poorly understood. Here we have developed a construct with a recombination substrate in which levels of recombination can be studied in the presence or absence of transcription. We observed a direct enhancement in recombination when transcription levels through the substrate were increased. This increase in homologous recombination following transcription is locus specific, since homologous recombination at the unrelated hprt gene is unaffected. In addition, we have shown that transcription-associated recombination involves both short-tract and long-tract gene conversions in mammalian cells, which are different from double-strand-break-induced recombination events caused by endonucleases. Transcription fails to enhance recombination in cells that are not in the S phase of the cell cycle. Furthermore, inhibition of transcription suppresses induction of recombination at stalled replication forks, suggesting that recombination may be involved in bypassing transcription during replication.

  • 34. Gottipati, Ponnari
    et al.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription-associated recombination in eukaryotes: link between transcription, replication and recombination.2009In: Mutagenesis, ISSN 1464-3804, Vol. 24, no 3, p. 203-10Article in journal (Refereed)
    Abstract [en]

    Homologous recombination (HR) is an important DNA repair pathway and is essential for cellular survival. It plays a major role in repairing replication-associated lesions and is functionally connected to replication. Transcription is another cellular process, which has emerged to have a connection with HR. Transcription enhances HR, which is a ubiquitous phenomenon referred to as transcription-associated recombination (TAR). Recent evidence suggests that TAR plays a role in inducing genetic instability, for example in the THO mutants (Tho2, Hpr1, Mft1 and Thp2) in yeast or during the development of the immune system leading to genetic diversity in mammals. On the other hand, evidence also suggests that TAR may play a role in preventing genetic instability in many different ways, one of which is by rescuing replication during transcription. Hence, TAR is a double-edged sword and plays a role in both preventing and inducing genetic instability. In spite of the interesting nature of TAR, the mechanism behind TAR has remained elusive. Recent advances in the area, however, suggest a link between TAR and replication and show specific genetic requirements for TAR that differ from regular HR. In this review, we aim to present the available evidence for TAR in both lower and higher eukaryotes and discuss its possible mechanisms, with emphasis on its connection with replication.

  • 35. Gottipati, Ponnari
    et al.
    Vischioni, Barbara
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Solomons, Joyce
    Bryant, Helen E.
    Djureinovic, Tatjana
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Issaeva, Natalia
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sleeth, Kate
    Sharma, Ricky A.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Poly(ADP-Ribose) Polymerase Is Hyperactivated in Homologous Recombination-Defective Cells2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 13, p. 5389-5398Article in journal (Refereed)
    Abstract [en]

    Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) is activated by DNA single-strand breaks (SSB) or at stalled replication forks to facilitate DNA repair. Inhibitors of PARP efficiently kill breast, ovarian, or prostate tumors in patients carrying hereditary mutations in the homologous recombination (HR) genes BRCA1 or BRCA2 through synthetic lethality. Here, we surprisingly show that PARP1 is hyperactivated in replicating BRCA2-defective cells. PARP1 hyperactivation is explained by the defect in HR as shRNA depletion of RAD54, RAD52, BLM, WRN, and XRCC3 proteins, which we here show are all essential for efficient HR and also caused PARP hyperactivation and correlated with an increased sensitivity to PARP inhibitors. BRCA2-defective cells were not found to have increased levels of SSBs, and PAR polymers formed in HR-defective cells do not colocalize to replication protein A or gamma H2AX, excluding the possibility that PARP hyperactivity is due to increased SSB repair or PARP induced at damaged replication forks. Resistance to PARP inhibitors can occur through genetic reversion in the BRCA2 gene. Here, we report that PARP inhibitor-resistant BRCA2-mutant cells revert back to normal levels of PARP activity. We speculate that the reason for the sensitivity of HR-defective cells to PARP inhibitors is related to the hyperactivated PARP1 in these cells. Furthermore, the presence of PAR polymers can be used to identify HR-defective cells that are sensitive to PARP inhibitors, which may be potential biomarkers. Cancer Res; 70(13); 5389-98. (C) 2010 AACR.

  • 36.
    Groth, Petra
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Auslander, Simon
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Majumder, Muntasir Mamun
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Petermann, Eva
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Methylated DNA Causes a Physical Block to Replication Forks Independently of Damage Signalling, O-6-Methylguanine or DNA Single-Strand Breaks and Results in DNA Damage2010In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 402, no 1, p. 70-82Article in journal (Refereed)
    Abstract [en]

    Even though DNA alkylating agents have been used for many decades in the treatment of cancer, it remains unclear what happens when replication forks encounter alkylated DNA. Here, we used the DNA fibre assay to study the impact of alkylating agents on replication fork progression. We found that the alkylator methyl methanesulfonate (MMS) inhibits replication elongation in a manner that is dose dependent and related to the overall alkylation grade. Replication forks seem to be completely blocked as no nucleotide incorporation can be detected following 1 h of MMS treatment. A high dose of 5 mM caffeine, inhibiting most DNA damage signalling, decreases replication rates overall but does not reverse MMS-induced replication inhibition, showing that the replication block is independent of DNA damage signalling. Furthermore, the block of replication fork progression does not correlate with the level of DNA single-strand breaks. Overexpression of O-6-methylguanine (O6meG)-DNA methyltransferase protein, responsible for removing the most toxic alkylation, O6meG, did not affect replication elongation following exposure to N-methyl-M-nitro-N-nitrosoguanidine. This demonstrates that O6meG lesions are efficiently bypassed in mammalian cells. In addition, we find that MMS-induced gamma H2AX foci co-localise with 53BP1 foci and newly replicated areas, suggesting that DNA double-strand breaks are formed at MMS-blocked replication forks. Altogether, our data suggest that N-alkylations formed during exposure to alkylating agents physically block replication fork elongation in mammalian cells, causing formation of replication-associated DNA lesions, likely double-strand breaks.

  • 37.
    Groth, Petra
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Elvers, Ingegerd
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Orta, M. L.
    Majumder, M. M.
    Lagerqvist, Anne
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Ionizing radiation induces replication-associated secondary DNA double-strand breaks that are substrates for homologous recombination repairManuscript (preprint) (Other academic)
  • 38.
    Gubanova, Evgenia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Science for Life Laboratory; Division of Translational Medicine and Chemical Biology; Department of Medical Biochemistry and Biophysics; Karolinska Institut; Stockholm, Sweden.
    Issaeva, Natalia
    Djureinovic, Tatjana
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    SMG-1 regulates senescence and suppresses epithelial-mesenchymal transitionManuscript (preprint) (Other academic)
  • 39.
    Hansen, Lasse Tengbjerg
    et al.
    Institute of Molecular Pathology, University of Copenhagen.
    Lundin, Cecilia
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Poulsen, Hans Skovgaard
    Section of Radiation Biology, The Finsen Center, University Hospital of Copenhagen.
    Sorensen, Claus Storgaard
    Institute of Cancer Biology, Danish Cancer Society.
    Petersen, Lone Norgård
    Institute of Molecular Pathology, University of Copenhagen.
    Spang-Thomsen, Mogens
    Institute of Molecular Pathology, University of Copenhagen.
    DNA Repair Rate and Etoposide (VP16) Resistance of Tumor Cell Subpopulations derived from a Single Human Small Cell Lung Cancer2003In: Lung Cancer, ISSN 0169-5002, Vol. 40, no 2, p. 157-64Article in journal (Refereed)
    Abstract [en]

    Two human small cell lung cancer (SCLC) subpopulations, CPH 54A, and CPH 54B, established from the same patient tumor by in vitro cloning, were investigated. The tumor was classified as intermediate-type SCLC. The cellular sensitivity to ionizing radiation (IR) was previously determined in the two sublines both in vivo and in vitro. Here we measured the etoposide (VP16) sensitivity together with the induction and repair of VP16- and IR-induced DNA double-strand breaks (DSBs). The two subpopulations were found to differ significantly in sensitivity to VP16, with the radioresistant 54B subline also being VP16 resistant. In order to explain the VP16 resistant phenotype several mechanisms where considered. The p53 status, P-glycoprotein, MRP, topoisomerase IIα, and Mre11 protein levels, as well as growth kinetics, provided no explanations of the observed VP16 resistance. In contrast, a significant difference in repair of both VP16- and IR-induced DSBs, together with a difference in the levels of the DSB repair proteins DNA-dependent protein kinase (DNA-PKcs) and RAD51 was observed. The VP16- and radioresistant 54B subline exhibited a pronounced higher repair rate of DSBs and higher protein levels of both DNA-PKcs and RAD51 compared with the sensitive 54A subline. We suggest, that different DSB repair rates among tumor cell subpopulations of individual SCLC tumors may be a major determinant for the variation in clinical treatment effect observed in human SCLC tumors of identical histological subtype.

  • 40. Hansen, Lasse Tengbjerg
    et al.
    Lundin, Cecilia
    Stockholm University.
    Spang-Thomsen, Mogens
    Petersen, Lone Nørgård
    Helleday, Thomas
    Stockholm University.
    The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer.2003In: Int J Cancer, ISSN 0020-7136, Vol. 105, no 4, p. 472-9Article in journal (Refereed)
  • 41. Hawtin, Rachael Elizabeth
    et al.
    Stockett, David Elliot
    Wong, Oi Kwan
    Lundin, Cecilia
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Fox, Judith Ann
    Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks2010In: ONCOTARGET, ISSN 1949-2553, Vol. 1, no 7, p. 606-619Article in journal (Refereed)
    Abstract [en]

    Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality.

  • 42.
    Helleday, T
    et al.
    Stockholm University.
    Arnaudeau, C
    Jenssen, D
    Stockholm University.
    A partial hprt gene duplication generated by non-homologous recombination in V79 Chinese hamster cells is eliminated by homologous recombination.1998In: J Mol Biol, ISSN 0022-2836, Vol. 279, no 4, p. 687-94Article in journal (Refereed)
  • 43.
    Helleday, T
    et al.
    Stockholm University.
    Arnaudeau, C
    Jenssen, D
    Stockholm University.
    Effects of carcinogenic agents upon different mechanisms for intragenic recombination in mammalian cells.1998In: Carcinogenesis, ISSN 0143-3334, Vol. 19, no 6, p. 973-8Article in journal (Refereed)
  • 44.
    Helleday, T
    et al.
    Stockholm University.
    Johansson, F
    Stockholm University.
    Jenssen, D
    Stockholm University.
    The DRAG test: an assay for detection of genotoxic damage.2001In: Altern Lab Anim, ISSN 0261-1929, Vol. 29, no 3, p. 233-41Article in journal (Refereed)
  • 45.
    Helleday, T
    et al.
    Stockholm University.
    Nilsson, R
    Stockholm University.
    Jenssen, D
    Stockholm University.
    Arsenic[III] and heavy metal ions induce intrachromosomal homologous recombination in the hprt gene of V79 Chinese hamster cells.2000In: Environ Mol Mutagen, ISSN 0893-6692, Vol. 35, no 2, p. 114-22Article in journal (Refereed)
  • 46.
    Helleday, T
    et al.
    Stockholm University.
    Tuominen, K L
    Bergman, A
    Jenssen, D
    Stockholm University.
    Brominated flame retardants induce intragenic recombination in mammalian cells.1999In: Mutat Res, ISSN 0027-5107, Vol. 439, no 2, p. 137-47Article in journal (Refereed)
  • 47.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Amplifying tumour-specific replication lesions by DNA repair inhibitors - a new era in targeted cancer therapy.2008In: Eur J Cancer, ISSN 0959-8049, Vol. 44, no 7, p. 921-7Article in journal (Refereed)
  • 48.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Homologous recombination in cancer development, treatment and development of drug resistance2010In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 31, no 6, p. 955-960Article in journal (Refereed)
    Abstract [en]

    Although DNA double-strand breaks (DSBs) are substrates for homologous recombination (HR) repair, it is becoming apparent that DNA lesions produced at replication forks, for instance by many anticancer drugs, are more significant substrates for HR repair. Cells defective in HR are hypersensitive to a wide variety of anticancer drugs, including those that do not produce DSBs. Several cancers have mutations in or epigenetically silenced HR genes, which explain the genetic instability that drives cancer development. There are an increasing number of reports suggesting that mutation or epigenetic silencing of HR genes explains the sensitivity of cancers to current chemotherapy treatments. Furthermore, there are also many examples of re-expression of HR genes in tumours to explain drug resistance. Emerging data suggest that there are several different subpathways of HR, which can compensate for each other. Unravelling the overlapping pathways in HR showed that BRCA1- and BRCA2-defective cells rely on the PARP protein for survival. This synthetic lethal interaction is now being exploited for selective treatment of BRCA1- and BRCA2-defective cancers with PARP inhibitors. Here, I discuss the diversity of HR and how it impacts on cancer with a particular focus on how HR can be exploited in future anticancer strategies.

  • 49.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mutagenesis: mutating a gene while reading it.2010In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 20, no 2, p. R57-8Article, review/survey (Refereed)
    Abstract [en]

    Is it possible to mutate DNA during transcription? A new study shows that UV-damaged DNA is deaminated during transcription, which is a probable mechanism underlying CC tandem mutations found in the p53 gene in skin cancers.

  • 50.
    Helleday, Thomas
    Stockholm University.
    Pathways for mitotic homologous recombination in mammalian cells.2003In: Mutat Res, ISSN 0027-5107, Vol. 532, no 1-2, p. 103-15Article, review/survey (Other (popular science, discussion, etc.))
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