title: Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence.
abstract: Genomic instability is a hallmark of aging tissues. Genomic instability may arise from the inefficient or aberrant function of DNA double-stranded break (DSB) repair. DSBs are repaired by homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). HR is a precise pathway, whereas NHEJ frequently leads to deletions or insertions at the repair site. Here, we used normal human fibroblasts with a chromosomally integrated HR reporter cassette to examine the changes in HR efficiency as cells progress to replicative senescence. We show that HR declines sharply with increasing replicative age, with an up to 38-fold decrease in efficiency in presenescent cells relative to young cells. This decline is not explained by a reduction of the number of cells in S/G(2)/M stage as presenescent cells are actively dividing. Expression of proteins involved in HR such as Rad51, Rad51C, Rad52, NBS1, and Sirtuin 6 (SIRT6) diminished with cellular senescence. Supplementation of Rad51, Rad51C, Rad52, and NBS1 proteins, either individually or in combination, did not rescue the senescence-related decline of HR. However, overexpression of SIRT6 in "middle-aged" and presenescent cells strongly stimulated HR repair, and this effect was dependent on mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). These results suggest that in aging cells, the precise HR pathway becomes repressed giving way to a more error-prone NHEJ pathway. These changes in the processing of DSBs may contribute to age-related genomic instability and a higher incidence of cancer with age. SIRT6 activation provides a potential therapeutic strategy to prevent the decline in genome maintenance.
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors: Zhiyong
authors: Z
authors: Mao
authors: Xiao
authors: X
authors: Tian
authors: Michael
authors: M
authors: Van Meter
authors: Zhonghe
authors: Z
authors: Ke
authors: Vera
authors: V
authors: Gorbunova
authors: Andrei
authors: A
authors: Seluanov
mesh_terms: D000367:Age Factors; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D005347:Fibroblasts; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D042822:Genomic Instability; D059765:Homologous Recombination / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D037761:Sirtuins / Q000378:metabolism*
chemical_list: C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C516592:SIRT6 protein, human; D037761:Sirtuins