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Published online 27 November 2006. doi:10.1083/jcb.200606145
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 5, 703-708
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Report

 Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination

Akira Motegi1, Raman Sood2, Helen Moinova3, Sanford D. Markowitz3,4, Pu Paul Liu2, and Kyungjae Myung1

1 Genome Instability Section and 2 Oncogenesis and Development Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
3 Department of Medicine and 4 Howard Hughes Medical Institute, Case Western Reserve University, Cleveland, OH 44106

Correspondence to Kyungjae Myung: kmyung{at}nhgri.nih.gov

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.

Abbreviations used in this paper: HEK, human embryonic kidney; MMC, mitomycin C; MMS, methyl methanesulfonate; PCNA, proliferating cell nuclear antigen; shRNA, short hairpin RNA; TLS, translesion synthesis.


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