S-Space College of Natural Sciences (자연과학대학) Dept. of Biological Sciences (생명과학부) Theses (Ph.D. / Sc.D._생명과학부)
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
- 자연과학대학 생명과학부
- Issue Date
- 서울대학교 대학원
- EFP (estrogen-responsive finger protein); ISG15 (interferon-stimulated gene 15); PCNA (proliferating cell nuclear antigen); Polymerase eta; Translesion DNA synthesis; USP10 (ubiquitin specific protease 10)
- 학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2014. 8. 정진하.
- 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.