Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination.
Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination.
复制标题
人类SHPRH通过增殖细胞核抗原多泛素化抑制基因组不稳定性。
DOI：
10.1083/jcb.200606145
复制
发表时间：
2006-12-04
影响因子：
7.8
通讯作者：
Myung, Kyungjae
中科院分区：
文献类型：
--
作者：
Motegi, Akira;Sood, Raman;Moinova, Helen;Markowitz, Sanford D;Liu, Pu Paul;Myung, Kyungjae
Differential modifications of proliferating cell nuclear antigen (PCNA) determine DNA repair pathways at stalled replication forks. In yeast, PCNA monoubiquitination by the ubiquitin ligase (E3) yRad18 promotes translesion synthesis (TLS), whereas the lysine-63–linked polyubiquitination of PCNA by yRad5 (E3) promotes the error-free mode of bypass. The yRad5-dependent pathway is important to prevent genomic instability during replication, although its exact molecular mechanism is poorly understood. This mechanism has remained totally elusive in mammals because of the lack of apparent RAD5 homologues. We report that a putative tumor suppressor gene, SHPRH, is a human orthologue of yeast RAD5. SHPRH associates with PCNA, RAD18, and the ubiquitin-conjugating enzyme UBC13 (E2) and promotes methyl methanesulfonate (MMS)–induced PCNA polyubiquitination. The reduction of SHPRH by stable short hairpin RNA increases sensitivity to MMS and enhances genomic instability. Therefore, the yRad5/SHPRH-dependent pathway is a conserved and fundamental DNA repair mechanism that protects the genome from genotoxic stress.
