Carcinogenesis Advance Access originally published online on May 29, 2009
Carcinogenesis 2009 30(8):1314-1319; doi:10.1093/carcin/bgp136
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Human RIF1 encodes an anti-apoptotic factor required for DNA repair
Laboratory of Cancer Biology, College of Life Sciences, Capital Normal University, 105 Xi San Huan Road (North), Beijing 100048, China
1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China
2 Division of Biology, City of Hope National Medical Center, Duarte, CA 91010, USA
3 Genome Stability Group, Beijing Institute of Genomics Chinese Academy of Sciences, Beijing 100029, China
4 Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
5 Division of Molecular and Clinical Pharmacology, City of Hope National Medical Center, Duarte, CA 91010, USA
* To whom correspondence should be addressed. Tel: +86 10 68902440; Fax: +86 10 68906307; Email: xingzhi_xu{at}mail.cnu.edu.cn
Human Rap1-interacting protein 1 (RIF1) contributes to the ataxia telangiectasia, mutated-mediated DNA damage response against the dexterous effect of DNA lesions and plays a critical role in the S-phase checkpoint. However, the molecular mechanisms by which human RIF1 conquers DNA aberrations remain largely unknown. We here showed that inhibition of RIF1 expression by small interfering RNA led to defective homologous recombination-mediated DNA double-strand break repair and sensitized cancer cells to camptothecin or staurosporine treatment. RIF1 underwent caspase-dependent cleavage upon apoptosis. We further found that RIF1 was highly expressed in human breast tumors, and its expression status was positively correlated with differentiation degrees of invasive ductal carcinoma of the breast. Our results suggest that RIF1 encodes an anti-apoptotic factor required for DNA repair and is a potential target for cancer treatment.
Abbreviations: ATM, ataxia telangiectasia, mutated; ChIP, chromatin immunoprecipitation; CPT, camptothecin; DSB, double-strand break; GFP, green fluorescent protein; HR, homologous recombination; IDC, invasive ductal carcinoma; IgG, immunoglobulin G; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; NHEJ, non-homologous end joining; PCR, polymerase chain reaction; RIF1, Rap1-interacting protein 1; siRNA, small interfering RNA; STS, staurosporine
These authors contributed equally to this work. Received April 16, 2009; revised May 12, 2009; accepted May 20, 2009.