title: PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress.
abstract: 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 CRL4CDT2 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 CRL4CDT2 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.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Ukhyun
authors.initials: U
authors.lastname: Jo
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Winson
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Jingming
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Department of Radiation Oncology and Center for DNA damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Hyungjin
authors.identifier: http://orcid.org/0000-0003-1913-6373
authors.initials: H
authors.lastname: Kim
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D054377:Chemokine CXCL12 / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics* / Q000378:metabolism; D055550:Protein Stability / Q000528:radiation effects; D059748:Proteolysis / Q000528:radiation effects; D016196:S Phase / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics / Q000528:radiation effects; D014466:Ultraviolet Rays; D053722:Receptors, Interleukin-17
chemical_list: D054377:Chemokine CXCL12; D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; D044767:Ubiquitin-Protein Ligases; C515255:CXCL12 protein, human; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17; C000618259:SDE2 protein, human