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Modification of PCNA by ISG15 Plays a Crucial Role in Termination of Error-Prone Translesion DNA Synthesis
ISG15에 의한 PCNA의 변형이 Error-Prone Translesion DNA Synthesis의 종결에 미치는 영향에 관한 연구

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Authors
박정미
Advisor
정진하
Major
자연과학대학 생명과학부
Issue Date
2014-08
Publisher
서울대학교 대학원
Keywords
EFP (estrogen-responsive finger protein)ISG15 (interferon-stimulated gene 15)PCNA (proliferating cell nuclear antigen)Polymerase etaTranslesion DNA synthesisUSP10 (ubiquitin specific protease 10)
Description
학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2014. 8. 정진하.
Abstract
In response to DNA damage, PCNA is mono-ubiquitinated and triggers translesion DNA synthesis (TLS) by recruiting polymerase-. However, it remained unknown how error-prone TLS is turned off after DNA lesion bypass to prevent mutagenesis. Here, I 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- 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- to nuclear foci, causing an increase in mutation frequency and in turn a decrease in cell survival. These findings establish a crucial role of PCNA ISGylation in termination of error-prone TLS for preventing excessive mutagenesis and thereby for the maintenance of genome stability.
Language
English
URI
https://hdl.handle.net/10371/121397
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College of Natural Sciences (자연과학대학)Dept. of Biological Sciences (생명과학부)Theses (Ph.D. / Sc.D._생명과학부)
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