期刊
MOLECULAR CELL
卷 81, 期 3, 页码 442-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.11.029
关键词
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资金
- Novo Nordisk Foundation [NNF16CC0020906, NNF18OC0030752, NNF14CC0001]
- European Research Council (ERC) under the European Union [715975]
- Lundbeck Foundation [R303-2018-3212]
- European Research Council (ERC) [715975] Funding Source: European Research Council (ERC)
RFWD3 is an E3 ubiquitin ligase that promotes ubiquitylation of proteins on ssDNA, and its absence inhibits PCNA ubiquitylation and affects TLS. This suggests that RFWD3 is an essential coordinator in the response to ssDNA gaps.
Lesions on DNA uncouple DNA synthesis from the replisome, generating stretches of unreplicated single-stranded DNA (ssDNA) behind the replication fork. These ssDNA gaps need to be filled in to complete DNA duplication. Gap-filling synthesis involves either translesion DNA synthesis (TLS) or template switching (TS). Controlling these processes, ubiquitylated PCNA recruits many proteins that dictate pathway choice, but the enzymes regulating PCNA ubiquitylation in vertebrates remain poorly defined. Here we report that the E3 ubiquitin ligase RFWD3 promotes ubiquitylation of proteins on ssDNA. The absence of RFWD3 leads to a profound defect in recruitment of key repair and signaling factors to damaged chromatin. As a result, PCNA ubiquitylation is inhibited without RFWD3, and TLS across different DNA lesions is drastically impaired. We propose that RFWD3 is an essential coordinator of the response to ssDNA gaps, where it promotes ubiquitylation to drive recruitment of effectors of PCNA ubiquitylation and DNA damage bypass.
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