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.
Highlights
Replication stress caused by aberrant DNA replication is a major source of genome instability [1]
The CRL4CDT2 ubiquitin E3 ligase plays a unique role in this pathway by coupling proteolysis to interaction with the DNA replication processivity factor Proliferating cell nuclear antigen (PCNA), in order to ensure selective elimination of key factors in cell cycle regulation
We identify a new human protein called SDE2 that helps cells relieve replication stress and ensure completing DNA replication process, whose activity is regulated by PCNA interaction and CRL4CDT2
Summary
Replication stress caused by aberrant DNA replication is a major source of genome instability [1]. DNA mutations and chromosome aberrations arising from stalled and collapsed replication forks are closely associated with tumorigenesis [2] To counteract these genotoxic threats, cells make a concerted effort to activate cell cycle checkpoints and execute DNA repair, processes that are collectively referred to as the DNA damage response (DDR) [3]. PCNA monoubiquitination triggers TLS to directly bypass base damage and temporarily relieve arrested DNA replication using low-fidelity TLS polymerases that can accommodate various types of template structures [4]. In this mechanism, single-stranded (ss) DNA generated at stalled replication forks activates RAD18 ubiquitin E3 ligase to monoubiquitinate PCNA [5,6]. Deregulation of PCNA deubiquitination caused by a deficiency of the deubiquitinating enzyme (DUB) ubiquitin-specific protease 1 (USP1) leads to disruption of TLS and increased genome instability due to the spurious recruitment of TLS polymerases [17]
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