Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA  

作　　者：Parker L Andersen Fang Xu Wei Xiao 

机构地区：[1]Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E5, USA [2]Department of Biology, Ningxia Medical College, Yinchuan, Ningxia 750004, China

出　　处：《Cell Research》2008年第1期162-173,共12页细胞研究（英文版）

基　　金：Acknowledgments The authors wish to thank Landon Pastushok, Michelle Hanna and other members from the Xiao laboratory for helpful discussion. This work was supported by the Canadian Institutes of Health Research operating grants MOP-38104 and MOP-53240 to W Xiao, and the National Natural Science Foundation of China（Grant no. 30560132） to F Xu.

摘　　要：In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance （DDT） has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen （PCNA） by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis （TLS） with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer.

关 键 词：DNA damage tolerance translesion synthesis Y-family polymerase UBIQUITINATION SUMOYLATION PCNA 

分 类 号：Q523[生物学—生物化学]