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Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks

Rageul, Julie and Park, Jennifer J. and Jo, Ukhyun and Weinheimer, Alexandra S. and Vu, Tri T. M. and Kim, Hyungjin (2019) Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks. Nucleic Acids Research, 47 (8). pp. 3996-4010. ISSN 0305-1048. PMCID PMC6486553. doi:10.1093/nar/gkz054.

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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-SDE2^(Ct), the C-terminal SDE2 fragment bearing an N-terminal Lys residue. Lys-SDE2^(Ct) 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/p97^(UFD1-NPL4) segregase cooperate to promote phosphorylation-dependent, chromatin-associated Lys-SDE2^(Ct) degradation upon UVC damage. Conversely, cells expressing the degradation-refractory K78V mutant, Val-SDE2^(Ct), 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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Vu, Tri T. M.0000-0002-1098-5646
Kim, Hyungjin0000-0003-1913-6373
Additional Information:© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 03 January 2019; Accepted: 24 January 2019; Published: 30 January 2019. We thank Dr. Alexander Varshavsky (Caltech) for his insightful discussion and reagents. We thank Dr. Daniel Durocher (The Lunenfeld-Tanenbaum Research Institute) for a cell line and Dr. Orlando Schärer (UNIST, Korea) for critically reading the manuscript. Funding: National Institutes of Health [CA218132]; American Cancer Society [RSG-18-037-01-DMC]; Concern Foundation; Carol M. Baldwin Breast Cancer Research Award; and Startup fund from the Research Foundation and the Cancer Center at Stony Brook University (to H.K.). Funding for open access charge: American Cancer Society. Conflict of interest statement. None declared.
Funding AgencyGrant Number
American Cancer SocietyRSG-18-037-01-DMC
Concern FoundationUNSPECIFIED
Carol M. Baldwin Breast Cancer Research FundUNSPECIFIED
Stony Brook UniversityUNSPECIFIED
Issue or Number:8
PubMed Central ID:PMC6486553
Record Number:CaltechAUTHORS:20190211-143119742
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Official Citation:Julie Rageul, Jennifer J Park, Ukhyun Jo, Alexandra S Weinheimer, Tri T M Vu, Hyungjin Kim, Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks, Nucleic Acids Research, Volume 47, Issue 8, 07 May 2019, Pages 3996–4010,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92835
Deposited By: Tony Diaz
Deposited On:12 Feb 2019 22:06
Last Modified:16 Nov 2021 03:54

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