S-Space College of Natural Sciences (자연과학대학) Dept. of Biological Sciences (생명과학부) Journal Papers (저널논문_생명과학부)
Modification of PCNA by ISG15 Plays a Crucial Role in Termination of Error-Prone Translesion DNA Synthesis
- Park, Jung Mi; Yang, Seung Wook; Yu, Kyung Ryun; Ka, Seung Hyun; Lee, Seong Won; Seol, Jae Hong; Jeon, Young Joo; Chung, Chin Ha
- Issue Date
- Molecular Cell, Vol.54 No.4, pp. 626-638
- 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.
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