한빛사 논문
Julie Rageul1, Jennifer J. Park1, Ukhyun Jo1, Alexandra S. Weinheimer2, Tri T.M. Vu3 and Hyungjin Kim1,4,*
1 Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA, 2 Biochemistry and Structural Biology graduate program, Stony Brook University, Stony Brook, NY 11794, USA, 3 Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA and 4 Stony Brook Cancer Center, Stony Brook School of Medicine, Stony Brook, NY 11794, USA
*To whom correspondence should be addressed.
Present address: Ukhyun Jo, Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Abstract
Multiple pathways counteract DNA replication stress to prevent genomic instability and tumorigenesis. The recently identified human SDE2 is a genome surveillance protein regulated by PCNA, a DNA clamp and processivity factor at replication forks. Here, we show that SDE2 cleavage after its ubiquitin-like domain generates Lys-SDE2Ct , the C-terminal SDE2 fragment bearing an N-terminal Lys residue. Lys-SDE2Ct constitutes a short-lived physiological substrate of the Arg/N-end rule proteolytic pathway, in which UBR1 and UBR2 ubiquitin ligases mediate the degradation. The Arg/N-end rule and VCP/p97UFD1-NPL4 segregase cooperate to promote phosphorylation-dependent, chromatin-associated Lys-SDE2Ct degradation upon UVC damage. Conversely, cells expressing the degradation-refractory K78V mutant, Val-SDE2Ct, fail to induce RPA phosphorylation and single-stranded DNA formation, leading to defects in PCNA-dependent DNA damage bypass and stalled fork recovery. Together, our study elucidates a previously unappreciated axis connecting the Arg/N-end rule and the p97-mediated proteolysis with the replication stress response, working together to preserve replication fork integrity.
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