title: REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1.
abstract: REV1 is a Y-family polymerase specialized for replicating across DNA lesions at the stalled replication folk. Due to the high error rate of REV1-dependent translesion DNA synthesis (TLS), tight regulation of REV1 activity is essential. Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. Surprisingly, polyubiquitination of REV1 also requires REV7, a TLS accessory protein that interacts with REV1 and other TLS polymerases. The N-terminal region of REV1 contains both the APC degron and an additional REV7-binding domain. Depletion of REV7 by RNA interference stabilizes REV1 by preventing polyubiquitination, whereas overexpression of REV7 augments REV1 degradation. Taken together, our findings suggest a role of REV7 in governing REV1 stability and interplay between TLS and APC-dependent proteolysis.
authors.affiliation: Department of Biochemistry and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Abel Chiu-Shun
authors.initials: AC
authors.lastname: Chun
authors.forename: Kin-Hang
authors.initials: KH
authors.lastname: Kok
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D064246:Mad2 Proteins; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination; D000099270:Y-Family DNA Polymerases
chemical_list: D064173:Anaphase-Promoting Complex-Cyclosome; D017931:DNA Primers; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; D046988:Proteasome Endopeptidase Complex; D011506:Proteins; D034741:RNA, Small Interfering; D043743:Ubiquitin-Protein Ligase Complexes; C120552:MAD2L2 protein, human; C429004:REV1 protein, human; D000099270:Y-Family DNA Polymerases
keywords: DNA damage tolerance; REV1; REV7; anaphase-promoting complex; translesion DNA synthesis