SHPRH and HLTF Act in a Damage-Specific Manner to Coordinate Different Forms of Postreplication Repair and Prevent Mutagenesis

被引:149
作者
Lin, Jia-Ren [1 ]
Zeman, Michelle K. [1 ]
Chen, Jia-Yun [1 ]
Yee, Muh-Ching [1 ]
Cimprich, Karlene A. [1 ]
机构
[1] Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
CELL NUCLEAR ANTIGEN; DNA-POLYMERASE-ETA; TRANSLESION SYNTHESIS; UBIQUITIN LIGASE; SACCHAROMYCES-CEREVISIAE; MONOUBIQUITINATED PCNA; GENOMIC INSTABILITY; REPLICATION FORK; THYMINE DIMER; POL-ETA;
D O I
10.1016/j.molcel.2011.02.026
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Postreplication repair (PRR) pathways play important roles in restarting stalled replication forks and regulating mutagenesis. In yeast, Rad5-mediated damage avoidance and Rad1 8-mediated translesion synthesis (TLS) are two forms of PRR. Two Rad5-related proteins, SHPRH and HLTF, have been identified in mammalian cells, but their specific roles in PRR are unclear. Here, we show that HLTF and SHPRH suppress mutagenesis in a damage-specific manner, preventing mutations induced by UV and MMS, respectively. Following UV, HLTF enhances PCNA monoubiquitination and recruitment of TLS polymerase eta, while also inhibiting SHPRH function. In contrast, MMS promotes the degradation of HLTF and the interactions of SHPRH with Rad18 and polymerase kappa. Our data suggest not only that cells differentially utilize HLTF and SHPRH for different forms of DNA damage, but also, surprisingly, that HLTF and SHPRH may coordinate the two main branches of PRR to choose the proper bypass mechanism for minimizing mutagenesis.
引用
收藏
页码:237 / 249
页数:13
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