title: The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction.
abstract: Rad51C is a central component of two complexes formed by five Rad51 paralogs in vertebrates. These complexes are involved in repairing DNA double-strand breaks through homologous recombination. Despite accumulating evidence suggesting that the paralogs may prevent aneuploidy by controlling centrosome integrity, Rad51C's role in maintaining chromosome stability remains unclear. Here we demonstrate that Rad51C deficiency leads to both centrosome aberrations in an ATR-Chk1-dependent manner and increased aneuploidy in human cells. While it was reported that Rad51C deficiency did not cause centrosome aberrations in interphase in hamster cells, such aberrations were observed in interphase in HCT116 cells with Rad51C dysfunction. Caffeine treatment and down-regulation of ATR, but not that of ATM, reduced the frequency of centrosome aberrations in the mutant cells. Silencing of Rad51C by RNA interference in HT1080 cells resulted in similar aberrations. Treatment with a Chk1 inhibitor and silencing of Chk1 also reduced the frequency in HCT116 mutants. Accumulation of Chk1 at the centrosome and nuclear foci of gamma H2AX were increased in the mutants. Moreover, the mutant cells had a higher frequency of aneuploidy. These findings indicate that the ATR-Chk1 pathway plays a role in increased centrosome aberrations induced by Rad51C dysfunction.
authors.affiliation: Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Katsura
authors.forename: Takanori
authors.initials: T
authors.lastname: Tsuruga
authors.forename: Osamu
authors.initials: O
authors.lastname: Date
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshihara
authors.forename: Mari
authors.initials: M
authors.lastname: Ishida
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tomoda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Okajima
authors.forename: Motoki
authors.initials: M
authors.lastname: Takaku
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurumizaka
authors.forename: Aiko
authors.initials: A
authors.lastname: Kinomura
authors.forename: Hiromu K
authors.initials: HK
authors.lastname: Mishima
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Miyagawa
mesh_terms: D000782:Aneuploidy; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000648:ultrastructure*; D000071877:Checkpoint Kinase 1; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D011995:Recombination, Genetic
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C448305:RAD51C protein, human; C110901:X-ray repair cross complementing protein 3; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases