title: Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes.
abstract: The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Du
authors.forename: Johnny
authors.initials: J
authors.lastname: Shen
authors.forename: Nishan
authors.initials: N
authors.lastname: Kugan
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Catherine
authors.initials: C
authors.lastname: Cheung
authors.forename: Sally
authors.initials: S
authors.lastname: Pak
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: F Brad
authors.initials: FB
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001816:Bloom Syndrome / Q000235:genetics / Q000378:metabolism*; D001824:Body Constitution / Q000235:genetics / Q000502:physiology; D007246:Infertility / Q000235:genetics / Q000378:metabolism; D007421:Intestine, Small / Q000473:pathology; D008136:Longevity / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D009154:Mutation; D012313:RNA / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D013737:Testis / Q000473:pathology; D014898:Werner Syndrome / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase