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  • 1.
    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. 

  • 2.
    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)
  • 3.
    Issaeva, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Thomas, Huw D.
    Djurenovic, Tatjana
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jaspers, Janneke E.
    Stoimenov, Ivaylo
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Kyle, Suzanne
    Pedley, Nicholas
    Gottipati, Ponnari
    Zur, Rafal
    Sleeth, Kate
    Chatzakos, Vicky
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mulligan, Evan A.
    Lundin, Cecilia
    Gubanova, Evgenia
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Kersbergen, Ariena
    Harris, Adrian L.
    Sharma, Ricky A.
    Rottenberg, Sven
    Curtin, Nicola J.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 15, p. 6268-6276Article in journal (Refereed)
    Abstract [en]

    Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy. Cancer Res; 70(15); 6268-76. (C) 2010 AACR.

  • 4.
    Stoimenov, Ivaylo
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Interplay between Transcription and Homologous Recombination in the Presence of DNA Damage2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The biochemical processes of DNA repair, replication and recombination compete for the same substrate, the DNA molecule. This competition is natural, as each process requires the same template. In order to resolve possible conflicts between these processes, when they take place on a particular stretch of DNA, certain crosstalk is expected. The complexity is additionally increased by the existence of another DNA dependent process, which occurs in all phases of the cell cycle: transcription.

    This thesis aims to investigate the link between transcription inhibition and homologous recombination, especially in the context of UV-induced DNA damage. The results show that the transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) induces homologous recombination. The DNA damage caused by UVC irradiation is repaired mainly via nucleotide excision repair, however, it is also known to trigger recombinational repair. In the presence of UV-induced damage, transcription inhibition by DRB potentiates the induction of homologous recombination as a necessary mechanism of cell survival.

    The thesis also focuses on the toxicity mechanisms of the chemotherapeutic compound 6-thioguanine (6TG). The work in the thesis suggests application of 6TG as a treatment for hereditary forms of breast cancer, with genetically altered BRCA1 or BRCA2 functions. Most importantly, the treatment with 6TG is applicable to breast cancers, which have developed resistance to another class of chemotherapeutic drugs, poly-(ADP-ribose) polymerase (PARP) inhibitors. Repair of the DNA damage induced by 6TG treatment is investigated further with a particular focus the pathway of DNA damage avoidance involving DNA polymerase η. The function of DNA polymerase η seems to be an important factor for the outcome of DNA repair after 6TG exposure. The deficiency of DNA polymerase η is also investigated in connection with normal replication and the repair of UV-induced DNA damage.

    In summary, the work in the thesis sheds more light onto the fundamental connections between DNA replication, recombination, transcription, repair and damage avoidance. On a more practical side, the information obtained about these fundamental connections is used to suggest a possible therapy for several forms of breast cancer.

  • 5.
    Stoimenov, Ivaylo
    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.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Polymerase η proficiency sensitises cells to 6-thioguanineManuscript (preprint) (Other academic)
    Abstract [en]

    Severe photosensitivity of the skin and predisposition to cancer development are two important features whichcharacterising a genetic syndrome known as Xeroderma pigmentosum. An interesting class of patients has beendescribed, characterised by a proficiency in nucleotide excision repair and a defect in the DNA damage avoidancepathways. This class is termed Xeroderma pigmentosum variant (XP-V) and is known to be caused by a deficiencyin the function of the specific DNA Polymerase η. Cells derived from XP-V patients are sensitivie not only to UVlight but also to crosslinkers such as cisplatin, and Polη overexpression is potentially relevant to development ofcisplatin resistance. In this paper we investigate the importance of the Polη status in the response to treatment withthe chemotherapeutic agent 6-thioguanine (6TG). Our results show that Polη deficient cells are more resistant totreatment with 6TG in comparison to Polη complemented cells. This is in contrast to the typical UV sensitivity ofPolη deficient cells, which is confirmed in the same cells. We also show that 6TG has a growth retardation effect,regardless of the Polη status. There were no DNA double-strand breaks detected in a short period after theexposure to 6TG in physiologically relevant doses, although a DNA damage response was observed in high doses.It was previously demonstrated that 6TG can be used to kill cisplatin resistant cells and these data may indicateone potential explanation.

  • 6.
    Stoimenov, Ivaylo
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gottipai, Ponnari
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Savolainen, Linda
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Niklas, Schultz
    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 UV-induced DNA damage triggers futile homologous recombination repair in mammalian cellsManuscript (preprint) (Other academic)
  • 7.
    Stoimenov, Ivaylo
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gottipati, Ponnari
    Schultz, Niklas
    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 inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) causes DNA damage and triggers homologous recombination repair in mammalian cells2011In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 706, no 1-2, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Transcription, replication and homologous recombination are intrinsically connected and it is well established that an increase of transcription is associated with an increase in homologous recombination. Here, we have studied how homologous recombination is affected during transcription inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), a compound that prevents activating phosphorylations of the RNA Pol II C-terminal domain. We identify that DRB triggers an increase in homologous recombination within the hprt gene as well as increasing RAD51 foci formation in mammalian cells. Furthermore, we find that DRB-induced transcriptional stress is associated with formation of the nuclear foci of the phosphorylated form of H2AX (γH2AX). We accounted that about 72% of RAD51 foci co-localized with the observed γH2AX foci. Interestingly, we find that XRCC3 mutated, homologous recombination defective cells are hypersensitive to the toxic effect of DRB and fail to form RAD51 foci. In conclusion, we show that DRB-induced transcription inhibition is associated with the formation of a lesion that triggers RAD51-dependent homologous recombination repair, required for survival under transcriptional stress.

  • 8.
    Stoimenov, Ivaylo
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    PCNA on the crossroad of cancer.2009In: Biochemical Society transactions, ISSN 1470-8752, Vol. 37, no Pt 3, p. 605-13Article in journal (Refereed)
    Abstract [en]

    Cancer is caused by genetic changes that often arise following failure to accurately replicate the DNA. PCNA (proliferating-cell nuclear antigen) forms a ring around the DNA to facilitate and control DNA replication. Emerging evidence suggests that PCNA is at the very heart of many essential cellular processes, such as DNA replication, repair of DNA damage, chromatin structure maintenance, chromosome segregation and cell-cycle progression. Progression of the DNA replication forks can be blocked by DNA lesions, formed either by endogenous damage or by exogenous agents, for instance anticancer drugs. Cellular response often results in change of PCNA function triggered either by specific post-translational modification of PCNA (i.e. ubiquitylation) or by exchange of its interaction partners. This puts PCNA in a central position in determining the fate of the replication fork. In the present article, we review PCNA modifications and interaction partners, and how those influence the course of events at replication forks, which ultimately determines both tumour progression as well as the outcome of anticancer treatment.

  • 9.
    Stoimenov, Ivaylo
    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.
    Gottipati, Ponnari
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription Inhibition by DRB Potentiates Recombinational Repair of UV Lesions in Mammalian Cells2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 5, p. e19492-Article in journal (Refereed)
    Abstract [en]

    Homologous recombination (HR) is intricately associated with replication, transcription and DNA repair in all organisms studied. However, the interplay between all these processes occurring simultaneously on the same DNA molecule is still poorly understood. Here, we study the interplay between transcription and HR during ultraviolet light (UV)-induced DNA damage in mammalian cells. Our results show that inhibition of transcription with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) increases the number of UV-induced DNA lesions (gamma H2AX, 53BP1 foci formation), which correlates with a decrease in the survival of wild type or nucleotide excision repair defective cells. Furthermore, we observe an increase in RAD51 foci formation, suggesting HR is triggered in response to an increase in UV-induced DSBs, while inhibiting transcription. Unexpectedly, we observe that DRB fails to sensitise HR defective cells to UV treatment. Thus, increased RAD51 foci formation correlates with increased cell death, suggesting the existence of a futile HR repair of UV-induced DSBs which is linked to transcription inhibition.

  • 10.
    Stoimenov, Ivaylo
    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.
    Gottipati, Ponnari
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription inhibition by DRB potentiates recombinational repair of UVC lesions in mammalian cellsManuscript (preprint) (Other academic)
1 - 10 of 10
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