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Title: Nonenzymatic Role for WRN in Preserving Nascent DNA Strands after Replication Stress

Journal Article · · Cell Reports
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  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. Kyoto Univ. (Japan)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
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WRN, the protein defective in Werner syndrome (WS), is a multifunctional nuclease involved in DNA damage repair, replication, and genome stability maintenance. It was assumed that the nuclease activities of WRN were critical for these functions. Here, we report a nonenzymatic role for WRN in preserving nascent DNA strands following replication stress. We found that lack of WRN led to shortening of nascent DNA strands after replication stress. Furthermore, we discovered that the exonuclease activity of MRE11 was responsible for the shortening of newly replicated DNA in the absence of WRN. Mechanistically, the N-terminal FHA domain of NBS1 recruits WRN to replication-associated DNA double-stranded breaks to stabilize Rad51 and to limit the nuclease activity of its C-terminal binding partner MRE11. Thus, this previously unrecognized nonenzymatic function of WRN in the stabilization of nascent DNA strands sheds light on the molecular reason for the origin of genome instability in WS individuals.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE; National Institutes of Health (NIH); National Aeronautics and Space Administration (NASA)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1207937
Journal Information:
Cell Reports, Vol. 9, Issue 4; ISSN 2211-1247
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 48 works
Citation information provided by
Web of Science

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WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations journal May 2010
Hydroxyurea-Stalled Replication Forks Become Progressively Inactivated and Require Two Different RAD51-Mediated Pathways for Restart and Repair journal February 2010
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Cited By (16)

RAD51 interconnects between DNA replication, DNA repair and immunity journal February 2017
FANCD2 influences replication fork processes and genome stability in response to clustered DSBs journal June 2015
A game of substrates: replication fork remodeling and its roles in genome stability and chemo-resistance journal December 2017
Rad9/53 BP 1 protects stalled replication forks from degradation in Mec1/ ATR ‐defective cells journal January 2018
The WRN exonuclease domain protects nascent strands from pathological MRE11/EXO1-dependent degradation journal August 2015
Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate replication restart journal September 2015
Transcriptional elongation requires DNA break-induced signalling journal December 2015
Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway journal December 2015
High expression of RAD51 promotes DNA damage repair and survival in KRAS-mutant lung cancer cells journal February 2019
Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype journal March 2017
Replication stress: getting back on track journal February 2016
Non-enzymatic roles of human RAD51 at stalled replication forks journal September 2019
Holding All the Cards—How Fanconi Anemia Proteins Deal with Replication Stress and Preserve Genomic Stability journal February 2019
Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation journal November 2015
Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments journal July 2018
Processing of DNA Ends in the Maintenance of Genome Stability journal September 2018

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