title: WRN regulates pathway choice between classical and alternative non-homologous end joining.
abstract: Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5' end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions.
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Raghavendra A
authors.initials: RA
authors.lastname: Shamanna
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: de Freitas
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Tian
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D006801:Humans; D000076228:MRE11 Homologue Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071657:Werner Syndrome Helicase / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D004706:Endodeoxyribonucleases; D000076228:MRE11 Homologue Protein; C410741:RBBP8 protein, human; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase