Change search
ReferencesLink to record
Permanent link

Direct link
Poly(ADP-Ribose) Polymerase Is Hyperactivated in Homologous Recombination-Defective Cells
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Show others and affiliations
2010 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 13, 5389-5398 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2010. Vol. 70, no 13, 5389-5398 p.
National Category
Natural Sciences
URN: urn:nbn:se:su:diva-50302DOI: 10.1158/0008-5472.CAN-09-4716ISI: 000279396800021OAI: diva2:380800
authorCount :10Available from: 2010-12-22 Created: 2010-12-22 Last updated: 2010-12-22Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Schultz, NiklasHelleday, Thomas
By organisation
Department of Genetics, Microbiology and Toxicology
In the same journal
Cancer Research
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 109 hits
ReferencesLink to record
Permanent link

Direct link