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Nucleic Acids Research Advance Access published online on February 19, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp082
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair, and Replication

RAD18 promotes DNA double-strand break repair during G1 phase through chromatin retention of 53BP1

Kenji Watanabe1, Kuniyoshi Iwabuchi2, Jinghua Sun1, Yuri Tsuji1,3, Tokio Tani4, Kazuaki Tokunaga4, Takayasu Date2, Mitsumasa Hashimoto2, Masaru Yamaizumi1,{dagger} and Satoshi Tateishi1,*

1Cell Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, 2Department of Biochemistry, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa 920-0293, 3Department of Oral and Maxillofacial Surgery, Sensory and Motor Organs Sciences, Faculty of Medicine and Pharmaceutical Sciences, Kumamoto University, Kumamoto 860-0811 and 4Department of Biological Science, Faculty of Science, Kumamoto University, Kumamoto 860-8555, Japan

*To whom correspondence should be addressed. Tel: +81 96 373 6602; Fax: +81 96 373 6604; Email: tate{at}gpo.kumamoto-u.ac.jp

Received September 17, 2008. Revised January 14, 2009. Accepted January 28, 2009.

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 {gamma}-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.

{dagger}Dr M. Yamaizumi died in May 2006.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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