Open AccessPCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress
Author(s) -
Ukhyun Jo,
Cai Winson,
Jingming Wang,
Kwon Yoojin,
Alan D. D’Andrea,
Hyungjin Kim
Publication year - 2016
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1006465
Subject(s) - proliferating cell nuclear antigen , biology , deubiquitinating enzyme , dna replication , replication factor c , dna repair , dna damage , microbiology and biotechnology , ubiquitin , eukaryotic dna replication , processivity , ubiquitin ligase , genome instability , dna re replication , replication protein a , cell cycle , dna , genetics , dna binding protein , cell , transcription factor , gene
Maintaining genomic integrity during DNA replication is essential for cellular survival and for preventing tumorigenesis. Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for DNA replication, and posttranslational modification of PCNA plays a key role in coordinating DNA repair against replication-blocking lesions by providing a platform to recruit factors required for DNA repair and cell cycle control. Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. SDE2 contains an N-terminal ubiquitin-like (UBL) fold, which is cleaved at a diglycine motif via a PCNA-interacting peptide (PIP) box and deubiquitinating enzyme activity. The cleaved SDE2 is required for negatively regulating ultraviolet damage-inducible PCNA monoubiquitination and counteracting replication stress. The cleaved SDE2 products need to be degraded by the CRL4 CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. Collectively, this study uncovers a new role for CRL4 CDT2 in protecting genomic integrity against replication stress via regulated proteolysis of PCNA-associated SDE2 and provides insights into how an integrated UBL domain within linear polypeptide sequence controls protein stability and function.