Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

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

Journal Article · · Cell Reports
 [1];  [1];  [1];  [1];  [1];  [2];  [3];  [1];  [1]
  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)
+ Show Author Affiliations
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:
NASA, Washington, DC (United States); National Institute of Health (NIH), New York, NY (United States); USDOE
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1207937
Journal Information:
Cell Reports, Journal Name: Cell Reports Journal Issue: 4 Vol. 9; ISSN 2211-1247
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

References (58)

A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1/2 journal July 2012
Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11 journal June 2011
DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial Drugs journal May 2010
Substrate specific stimulation of NEIL1 by WRN but not the other human RecQ helicases journal June 2010
Werner syndrome protein associates with γH2AX in a manner that depends upon Nbs1 journal January 2005
Hydroxyurea-Stalled Replication Forks Become Progressively Inactivated and Require Two Different RAD51-Mediated Pathways for Restart and Repair journal February 2010
ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery journal August 2010
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis journal April 2005
Topoisomerase I poisoning results in PARP-mediated replication fork reversal journal March 2012
Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition journal February 2013
Identification of a Coiled Coil in Werner Syndrome Protein That Facilitates Multimerization and Promotes Exonuclease Processivity journal August 2010
WRN Interacts Physically and Functionally with the Recombination Mediator Protein RAD52 journal September 2003
Werner Syndrome Protein Contains Three Structure-specific DNA Binding Domains journal December 2003
Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle journal August 2001
Werner syndrome diploid fibroblasts are sensitive to 4‐nitroquinoline‐N‐oxide and 8‐methoxypsoralen: implications for the disease phenotype journal March 2002
Cytogenet Genome Res of Werner’s syndrome cultured skin fibroblasts: variegated translocation mosaicism journal January 1981
The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome journal June 2011
Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis text January 2010
Werner syndrome protein, the MRE11 complex and ATR: menage-à-trois in guarding genome stability during DNA replication?: Hypothesis journal February 2004
Rad51 overexpression rescues radiation resistance in BRCA2-defective cancer cells journal February 2009
WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations journal May 2010
Werner syndrome lymphoblastoid cells are sensitive to camptothecin-induced apoptosis in S-phase journal February 1999
Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines journal October 1992
Hierarchical deterioration of body systems in Werner's syndrome: Implications for normal ageing journal December 1997
Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11 journal May 2011
Low doses of alpha particles do not induce sister chromatid exchanges in bystander Chinese hamster cells defective in homologous recombination journal March 2008
Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling journal February 2013
WRN participates in translesion synthesis pathway through interaction with NBS1 journal June 2010
DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities journal January 2014
Inhibition of Homologous Recombination in Human Cells by Targeting RAD51 Recombinase journal March 2012
The premature ageing syndrome protein, WRN, is a 3′→5′ exonuclease journal October 1998
Counting RAD51 proteins disassembling from nucleoprotein filaments under tension journal December 2008
A forward chemical genetic screen reveals an inhibitor of the Mre11–Rad50–Nbs1 complex journal January 2008
The Werner syndrome protein is a DNA helicase journal September 1997
Pathways of mammalian replication fork restart journal September 2010
Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis journal October 2010
WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing journal April 2006
Homologous recombination repair is regulated by domains at the N- and C-terminus of NBS1 and is dissociated with ATM functions journal March 2007
Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51: Nuclear foci formation of Werner helicase journal May 2001
WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair journal August 2003
Mutator phenotype of Werner syndrome is characterized by extensive deletions. journal August 1989
A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity journal October 1998
Identification of a Coiled Coil in Werner Syndrome Protein That Facilitates Multimerization and Promotes Exonuclease Processivity journal August 2010
WRN Interacts Physically and Functionally with the Recombination Mediator Protein RAD52 journal September 2003
Werner Syndrome Protein Contains Three Structure-specific DNA Binding Domains journal December 2003
Linkage between Werner Syndrome Protein and the Mre11 Complex via Nbs1 journal May 2004
Defective Mre11-dependent Activation of Chk2 by Ataxia Telangiectasia Mutated in Colorectal Carcinoma Cells in Response to Replication-dependent DNA Double Strand Breaks journal October 2006
Ku complex interacts with and stimulates the Werner protein journal April 2000
Novel pro- and anti-recombination activities of the Bloom's syndrome helicase journal December 2007
RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments journal December 2007
The Essential Functions of Human Rad51 Are Independent of ATP Hydrolysis journal October 1999
Mutations in the WRN Gene in Mice Accelerate Mortality in a p53-Null Background journal May 2000
Accumulation of Werner protein at DNA double-strand breaks in human cells journal September 2005
Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest journal December 2006
WRN helicase regulates the ATR–CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I–DNA covalent complexes journal December 2011
Increased Chemotherapeutic Activity of Camptothecin in Cancer Cells by siRNA-Induced Silencing of WRN Helicase journal January 2007
The Werner Syndrome Protein Is Distinguished from the Bloom Syndrome Protein by Its Capacity to Tightly Bind Diverse DNA Structures journal January 2012
The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest journal March 2008

Cited By (16)

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

Similar Records

Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
Journal Article · Thu Dec 17 23:00:00 EST 2015 · Oncotarget · OSTI ID:1627989
DNA secondary structure of the released strand stimulates WRN helicase action on forked duplexes without coordinate action of WRN exonuclease
Journal Article · Fri Aug 12 00:00:00 EDT 2011 · Biochemical and Biophysical Research Communications · OSTI ID:22207444
WRN Exonuclease Structure, Molecular Mechanism, and DNA EndProcessing Role
Journal Article · Tue Feb 14 23:00:00 EST 2006 · Nature Structural and Molecular Biology · OSTI ID:891194

Related Subjects

59 BASIC BIOLOGICAL SCIENCES