Recognition of forked and single-stranded DNA structures by human RAD18 complexed with RAD6B protein triggers its recruitment to stalled replication forks

被引:54
作者
Tsuji, Yuri [1 ,2 ]
Watanabe, Kenji [1 ]
Araki, Kimi [1 ]
Shinohara, Masanori [2 ]
Yamagata, Yuriko [3 ]
Tsurimoto, Toshiki [4 ]
Hanaoka, Fumio [5 ,6 ]
Yamamura, Ken-ichi [1 ]
Yamaizumi, Masaru [1 ]
Tateishi, Satoshi [1 ]
机构
[1] Kumamoto Univ, Inst Mol Embryol & Genet, Kumamoto 8600811, Japan
[2] Kumamoto Univ, Dept Oral & Maxillofacial Surg, Fac Med & Pharmaceut Sci, Kumamoto 8600811, Japan
[3] Kumamoto Univ, Grad Sch Pharmaceut Sci, Kumamoto 8620973, Japan
[4] Kyushu Univ, Dept Biol, Sch Sci, Higashi Ku, Fukuoka 8128581, Japan
[5] Osaka Univ, Grad Sch Frontier Biosci, Osaka 5650871, Japan
[6] Japan Sci & Technol Agcy, SORST, Osaka 5650871, Japan
关键词
D O I
10.1111/j.1365-2443.2008.01176.x
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Post-replication DNA repair facilitates the resumption of DNA synthesis upon replication fork stalling at DNA damage sites. Despite the importance of RAD18 and polymerase eta (Pol eta) for post-replication repair (PRR), the molecular mechanisms by which these factors are recruited to stalled replication forks are not well understood. We present evidence that human RAD18 complexed with RAD6B protein preferentially binds to forked and single-stranded DNA (ssDNA) structures, which are known to be localized at stalled replication forks. The SAP domain of RAD18 (residues 248-282) is crucial for binding of RAD18 complexed with RAD6B to DNA substrates. RAD18 mutated in the SAP domain fails to accumulate at DNA damage sites in vivo and does not guide DNA Pol eta to stalled replication forks. The SAP domain is also required for the efficient mono-ubiquitination of PCNA. The SAP domain mutant fails to suppress the ultraviolet (UV)-sensitivity of Rad18-knockout cells. These results suggest that RAD18 complexed with RAD6B is recruited to stalled replication forks via interactions with forked DNA or long ssDNA structures, a process that is required for initiating PRR.
引用
收藏
页码:343 / 354
页数:12
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