Involvement of the splicing factor SART1 in the BRCA1-dependent homologous recombination repair of DNA double-strand breaks
Ozaki K. Kato R. Yasuhara T. Uchihara Y. Hirakawa M. Abe Y. Shibata H. Kawabata-Iwakawa R. Shakayeva A. Kot P. Miyagawa K. Suzuki K. Matsuda N. Shibata A. Yamauchi M.
December 2024Nature Research
Scientific Reports
2024#14Issue 1
Although previous studies have reported that pre-mRNA splicing factors (SFs) are involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), their exact role in promoting HR remains poorly understood. Here, we showed that SART1, an SF upregulated in several types of cancer, promotes DSB end resection, an essential first step of HR. The resection-promoting function of SART1 requires phosphorylation at threonine 430 and 695 by ATM/ATR. SART1 is recruited to DSB sites in a manner dependent on transcription and its RS domain. SART1 is epistatic with BRCA1, a major HR factor, in the promotion of resection, especially transcription-associated resection in the G2 phase. SART1 and BRCA1 accumulate at DSB sites in an interdependent manner, and epistatically counteract the resection blockade posed by 53BP1 and RIF1. Furthermore, chromosome analysis demonstrated that SART1 and BRCA1 epistatically suppressed genomic alterations caused by DSB misrepair in the G2 phase. Collectively, these results indicate that SART1 and BRCA1 cooperatively facilitate resection of DSBs arising in transcriptionally active genomic regions in the G2 phase, thereby promoting faithful repair by HR, and suppressing genome instability.
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Hospital Campus Laboratory, Radioisotope Center, Central Institute of Radioisotope Science and Safety Management, Kyushu University, Fukuoka, 812-8582, Japan
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
Laboratory of Genome Stress Response, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Sakyo-Ku, Kyoto, 606-8501, Japan
Signal Transduction Program, Gunma University Initiative for Advanced Research (GIAR), Gunma University, Gunma, Maebashi, 371-8511, Japan
Center for Radiation Research and Education, Nagasaki University, Nagasaki, 852-8523, Japan
Department of Radiation Biology and Protection, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan
Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Gunma University, Gunma, Maebashi, 371-8511, Japan
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8523, Japan
Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, 852-8523, Japan
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, 19104, PA, United States
Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Tokyo, 105-8512, Japan
School of Medicine, Nazarbayev University, Astana, 010000, Kazakhstan
Institute of Biochemistry, FB08, Justus Liebig University Giessen, Giessen, 35392, Germany
Hospital Campus Laboratory
Laboratory of Molecular Radiology
Laboratory of Genome Stress Response
Signal Transduction Program
Center for Radiation Research and Education
Department of Radiation Biology and Protection
Division of Genomics
Division of Integrated Oncology Research
Graduate School of Biomedical Sciences
Department of Radiation Medical Sciences
Department of Cancer Biology
Division of Molecular Oncological Pharmacy
School of Medicine
Institute of Biochemistry
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