Journal article
The USP1/UAF1 Complex Promotes Double-Strand Break Repair through Homologous Recombination
Molecular and cellular biology, Vol.31(12), pp.2462-2469
06/01/2011
DOI: 10.1128/MCB.05058-11
PMCID: PMC3133424
PMID: 21482670
Abstract
Protein ubiquitination plays a key role in the regulation of a variety of DNA repair mechanisms. Protein ubiquitination is controlled by the coordinate activity of ubiquitin ligases and deubiquitinating enzymes (DUBs). The deubiquitinating enzyme USP1 regulates DNA repair and the Fanconi anemia pathway through its association with its WD40 binding partner, UAF1, and through its deubiquitination of two critical DNA repair proteins, FANCD2-Ub and PCNA-Ub. To investigate the function of USP1 and UAF1, we generated USP1(-/-), UAF1(-/-/-), and USP1(-/-) UAF1(-/-/-) chicken DT40 cell clones. These three clones showed similar sensitivities to chemical cross-linking agents, to a topoisomerase poison, camptothecin, and to an inhibitor of poly(ADP-ribose) polymerase (PARP), indicating that the USP1/UAF1 complex is a regulator of the cellular response to DNA damage. The hypersensitivity to both camptothecin and a PARP inhibitor suggests that the USP1/UAF1 complex promotes homologous recombination (HR)-mediated double-strand break (DSB) repair. To gain insight into the mechanism of the USP1/UAF1 complex in HR, we inactivated the nonhomologous end-joining (NHEJ) pathway in UAF1-deficient cells. Disruption of NHEJ in UAF1-deficient cells restored cellular resistance to camptothecin and the PARP inhibitor. Our results indicate that the USP1/UAF1 complex promotes HR, at least in part by suppressing NHEJ.
Details
- Title: Subtitle
- The USP1/UAF1 Complex Promotes Double-Strand Break Repair through Homologous Recombination
- Creators
- Junko Murai - Kyoto UniversityKailin Yang - Dana-Farber Cancer InstituteDonniphat Dejsuphong - Dana-Farber Cancer InstituteKouji Hirota - Kyoto UniversityShunichi Takeda - Kyoto UniversityAlan D. D'Andrea - Harvard University
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.31(12), pp.2462-2469
- Publisher
- Amer Soc Microbiology
- DOI
- 10.1128/MCB.05058-11
- PMID
- 21482670
- PMCID
- PMC3133424
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Number of pages
- 8
- Grant note
- R01DK043889 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R37HL052725 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) TOYOBO Biotechnology Foundation P01CA092584; R01DK43889; R01HL52725 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 22687001 / Grants-in-Aid for Scientific Research; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of Science; Grants-in-Aid for Scientific Research (KAKENHI) P01CA092584 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 06/01/2011
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696575402771
Metrics
3 Record Views