Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Polymerase η proficiency sensitises cells to 6-thioguanine
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. (Thomas Helleday's research group)
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
(English)Manuscript (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.

Keyword [en]
Polη, 6-thioguanine, XP-V
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-54733OAI: oai:DiVA.org:su-54733DiVA: diva2:397376
Available from: 2011-02-14 Created: 2011-02-14 Last updated: 2011-02-16Bibliographically approved
In thesis
1. Interplay between Transcription and Homologous Recombination in the Presence of DNA Damage
Open this publication in new window or tab >>Interplay between Transcription and Homologous Recombination in the Presence of DNA Damage
2011 (English)Doctoral 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.

Place, publisher, year, edition, pages
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2011. 70 p.
Keyword
homologous recombination, transcription, DRB, UVC, 6-thioguanine, mammalian cells, BRCA1, BRCA2, PARP inhibitors, XP-V
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-54736 (URN)978-91-7447-217-2 (ISBN)
Public defence
2011-03-18, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.Available from: 2011-02-24 Created: 2011-02-14 Last updated: 2011-02-16Bibliographically approved

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Stoimenov, IvayloElvers, IngegerdHelleday, Thomas
By organisation
Department of Genetics, Microbiology and Toxicology
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 44 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf