title: Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress.
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.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Fengtao
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shibani
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yanyong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Mori
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Souparno
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Division of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Yoshida-konoecho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Yannone
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: asaithamby.aroumougame@utsouthwestern.edu.
authors.forename: Aroumougame
authors.initials: A
authors.lastname: Asaithamby
mesh_terms: D000818:Animals; D016466:CHO Cells; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism*; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051135:Rad51 Recombinase / Q000378:metabolism; D053484:RecQ Helicases / Q000737:chemistry / Q000378:metabolism*; D051716:Replication Protein A / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D013329:Structure-Activity Relationship; D000071657:Werner Syndrome Helicase
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D051716:Replication Protein A; D004247:DNA; D051135:Rad51 Recombinase; C516794:RPA2 protein, human; D005090:Exodeoxyribonucleases; D000076228:MRE11 Homologue Protein; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D002166:Camptothecin