期刊
NUCLEIC ACIDS RESEARCH
卷 40, 期 20, 页码 10394-10407出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks763
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Health and Labour Science Research Grants of Japan
- Mitsubishi Foundation
- Takeda Science Foundation
- JSPS KAKENHI [24310040]
- Grants-in-Aid for Scientific Research [22310037] Funding Source: KAKEN
Post-replication DNA repair in eukaryotes is regulated by ubiquitination of proliferating cell nuclear antigen (PCNA). Monoubiquitination catalyzed by RAD6-RAD18 (an E2-E3 complex) stimulates translesion DNA synthesis, whereas polyubiquitination, promoted by additional factors such as MMS2-UBC13 (a UEV-E2 complex) and HLTF (an E3 ligase), leads to template switching in humans. Here, using an in vitro ubiquitination reaction system reconstituted with purified human proteins, we demonstrated that PCNA is polyubiquitinated predominantly via en bloc transfer of a pre-formed ubiquitin (Ub) chain rather than by extension of the Ub chain on monoubiquitinated PCNA. Our results support a model in which HLTF forms a thiol-linked Ub chain on UBC13 (UBC13 similar to Ub(n)) and then transfers the chain to RAD6 similar to Ub, forming RAD6 similar to Ub(n+1). The resultant Ub chain is subsequently transferred to PCNA by RAD18. Thus, template switching may be promoted under certain circumstances in which both RAD18 and HLTF are coordinately recruited to sites of stalled replication.
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