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| Subject Categories: Genome Stability & Dynamics |
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| The EMBO Journal
(2002) 21, 5558–5566, doi: 10.1093/emboj/cdf534 |
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| RAD18 and RAD54 cooperatively contribute to maintenance of genomic stability in vertebrate cells |
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| Yukiko M. Yamashita1, 2, Takashi Okada1, 3, Takahiro Matsusaka4, Eiichiro Sonoda1, Guang Yu Zhao1, Kasumi Araki1, Satoshi Tateishi5, Masaru Yamaizumi5 and Shunichi Takeda1 |
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1 Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501 Japan 2 Present address: Department of Developmental Biology, Stanford University, 279 Campus Drive, Beckman Center, B300, Stanford University School of Medicine, Stanford, CA 94305, USA 3 Urology, Graduate School of Medicine, Kyoto University Konoe, Sakyo-ku, Kyoto 606-8507 Japan 4 Graduate School of Biostudies, Kyoto University, Kitashirakawa Oiwake, Sakyo-ku, Kyoto 606-8502 Japan 5 Institute of Molecular Embryology and Genetics, Kumamoto University, Kuhonji 4-24-1, Kumamoto 862-0976, Japan To whom correspondence should be addressed Shunichi Takeda, stakeda@rg.med.kyoto-u.ac.jp Received 14 May 2002; Revised 14 August 2002; Accepted 19 August 2002. |
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| Abstract |
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| Translesion DNA synthesis (TLS) and homologous DNA recombination (HR) are two major pathways that account for survival after post-replicational DNA damage. TLS functions by filling gaps on a daughter strand that remain after DNA replication caused by damage on the mother strand, while HR can repair gaps and breaks using the intact sister chromatid as a template. The RAD18 gene, which is conserved from lower eukaryotes to vertebrates, is essential for TLS in Saccharomyces cerevisiae. To investigate the role of RAD18, we disrupted RAD18 by gene targeting in the chicken B-lymphocyte line DT40. RAD18-/- cells are sensitive to various DNA-damaging agents including ultraviolet light and the cross-linking agent cisplatin, consistent with its role in TLS. Interestingly, elevated sister chromatid exchange, which reflects HR- mediated post-replicational repair, was observed in RAD18-/- cells during the cell cycle. Strikingly, double mutants of RAD18 and RAD54, a gene involved in HR, are synthetic lethal, although the single mutant in either gene can proliferate with nearly normal kinetics. These data suggest that RAD18 plays an essential role in maintaining chromosomal DNA in cooperation with the RAD54-dependent DNA repair pathway. |
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| Keywords: genome instability, homologous DNA recombination, post-replication repair, RAD18, translesion DNA synthesis |
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