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Cell Rep. 2014 Nov 20;9(4):1387-401. doi: 10.1016/j.celrep.2014.10.025. Epub 2014 Nov 6.

Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress.

Author information

1
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Division of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Yoshida-konoecho, Sakyo-ku, Kyoto 606-8501, Japan.
4
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
5
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: asaithamby.aroumougame@utsouthwestern.edu.

Abstract

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.

PMID:
25456133
PMCID:
PMC4782925
DOI:
10.1016/j.celrep.2014.10.025
[Indexed for MEDLINE]
Free PMC Article

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