TY - JOUR
T1 - Nonenzymatic Role for WRN in Preserving Nascent DNA Strands after Replication Stress
AU - Su, Fengtao
AU - Mukherjee, Shibani
AU - Yang, Yanyong
AU - Mori, Eiichiro
AU - Bhattacharya, Souparno
AU - Kobayashi, Junya
AU - Yannone, Steven M.
AU - Chen, David J.
AU - Asaithamby, Aroumougame
N1 - Funding Information:
We would like to thank Dr. Brad Johnson and Dr. Philip Leder for the WRN knockout and WRN Δhel/Δhel mouse strains, respectively. We also thank Drs. Claudia Wiese and David Schild for Rad51 shRNA and Rad51 K133R mutant plasmids. This work was supported by NIH Grant CA134991 (to D.J.C.) and the National Aeronautics and Space Association grants NNX13AD57G (to A.A.) and NNX11AC54G (to D.J.C. and A.A.).
Publisher Copyright:
© 2014 The Authors.
PY - 2014/11/20
Y1 - 2014/11/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2014.10.025
DO - 10.1016/j.celrep.2014.10.025
M3 - Article
C2 - 25456133
AN - SCOPUS:84912097040
SN - 2211-1247
VL - 9
SP - 1387
EP - 1401
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -