title: Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation.
abstract: Susceptibility to senescence caused by defective DNA repair is a major hallmark of progeroid syndrome patients, but molecular mechanisms of how defective DNA repair predisposes to senescence are largely unknown. We demonstrate here that suppression of DNA repair pathways extends the duration of Chk1-dependent G2 checkpoint activation and sensitizes cells to senescence through enhancement of mitosis skipping. Extension of G2 checkpoint activation by introduction of the TopBP1 activation domain and the nondegradable mutant of Claspin sensitizes cells to senescence. In contrast, a shortening of G2 checkpoint activation by expression of SIRT6 or depletion of OTUB2 reduces susceptibility to senescence. Fibroblasts from progeroid syndromes tested shows a correlation between an extension of G2 checkpoint activation and an increase in the susceptibility to senescence. These results suggest that extension of G2 checkpoint activation caused by defective DNA repair is critical for senescence predisposition in progeroid syndrome patients.
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors: Yoshikazu
authors: Y
authors: Johmura
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors: Emiri
authors: E
authors: Yamashita
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors: Midori
authors: M
authors: Shimada
authors: Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya-cho, Kasugai, Aichi 480-0392, Japan.
authors: Keiko
authors: K
authors: Nakanishi
authors: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.|Division of Cancer Cell Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Makoto
authors: M
authors: Nakanishi
mesh_terms: D016922:Cellular Senescence / Q000235:genetics; D000071877:Checkpoint Kinase 1 / Q000502:physiology*; D004260:DNA Repair; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans
chemical_list: C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1