RAD18 promotes DNA double-strand break repair during G1 phase through chromatin retention of 53BP1 |
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| Authors: | Kenji Watanabe Kuniyoshi Iwabuchi Jinghua Sun Yuri Tsuji Tokio Tani Kazuaki Tokunaga Takayasu Date Mitsumasa Hashimoto Masaru Yamaizumi and Satoshi Tateishi |
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| Institution: | 1.Cell Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, 2.Department of Biochemistry, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa 920-0293, 3.Department of Oral and Maxillofacial Surgery, Sensory and Motor Organs Sciences, Faculty of Medicine and Pharmaceutical Sciences, Kumamoto University, Kumamoto 860-0811 and 4.Department of Biological Science, Faculty of Science, Kumamoto University, Kumamoto 860-8555, Japan |
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| Abstract: | Recruitment of RAD18 to stalled replication forks facilitates monoubiquitination of PCNA during S-phase, promoting translesion synthesis at sites of UV irradiation-induced DNA damage. In this study, we show that RAD18 is also recruited to ionizing radiation (IR)-induced sites of DNA double-strand breaks (DSBs) forming foci which are co-localized with 53BP1, NBS1, phosphorylated ATM, BRCA1 and γ-H2AX. RAD18 associates with 53BP1 and is recruited to DSB sites in a 53BP1-dependent manner specifically during G1-phase, RAD18 monoubiquitinates KBD domain of 53BP1 at lysine 1268 in vitro. A monoubiquitination-resistant 53BP1 mutant harboring a substitution at lysine 1268 is not retained efficiently at the chromatin in the vicinity of DSBs. In Rad18-null cells, retention of 53BP1 foci, efficiency of DSB repair and post-irradiation viability are impaired compared with wild-type cells. Taken together, these results suggest that RAD18 promotes 53BP1-directed DSB repair by enhancing retention of 53BP1, possibly through an interaction between RAD18 and 53BP1 and the modification of 53BP1. |
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