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Modification of PCNA by ISG15 Plays a Crucial Role in Termination of Error-Prone Translesion DNA Synthesis
Cited 78 time in
Web of Science
Cited 81 time in Scopus
- Authors
- Issue Date
- 2014-05
- Publisher
- Elsevier
- Citation
- Molecular Cell, Vol.54 No.4, pp. 626-638
- Keywords
- 자연과학
- Abstract
- In response to DNA damage, PCNA is mono-ubiquitinated and triggers translesion DNA synthesis (TLS) by recruiting polymerase-eta. However, it remained unknown how error-prone TLS is turned off after DNA lesion bypass to prevent mutagenesis. Here we showed that ISG15 modification (ISGylation) of PCNA plays a key role in TLS termination. Upon UV irradiation, EFP, an ISG15 E3 ligase, bound to mono-ubiquitinated PCNA and promoted its ISGylation. ISGylated PCNA then tethered USP10 for deubiquitination and in turn the release of polymerase-h from PCNA. Eventually, PCNA was deISGylated by UBP43 for reloading of replicative DNA polymerases and resuming normal DNA replication. However, ISGylation-defective Lys-to-Arg mutations in PCNA or knockdown of any of ISG15, EFP, or USP10 led to persistent recruitment of mono-ubiquitinated PCNA and polymerase-eta to nuclear foci, causing an increase in mutation frequency. These findings establish a crucial role of PCNA ISGylation in termination of error-prone TLS for preventing excessive mutagenesis.
- ISSN
- 1097-2765
- Language
- English
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