title: A role for the spindle assembly checkpoint in the DNA damage response.
abstract: Spontaneous DNA damage poses a continuous threat to genomic integrity. If unchecked, genotoxic insults result in genomic instability, a hallmark of cancer cells. In eukaryotic cells a DNA Damage Response (DDR) detects and responds to genotoxic stress, acting as an anti-cancer barrier in humans. Among other actions, the DDR blocks the segregation of incompletely replicated or damaged chromosomes, thus preventing aneuploidy. In a work aimed at better understanding such S-M control, we recently showed that cells block anaphase through different control pathways. The S phase checkpoint kinase Mec1/ATR inhibits mitotic Cyclin Dependent Kinase activity through effector kinases Swe1/Wee1 and Rad53/Chk2. Cells also stabilize the levels of Pds1/securin to block sister chromatid segregation in response to DNA damage. We show here that Pds1/securin abundance is still secured when the S phase checkpoint response is fully abrogated in mec1/ATR tel1/ATM double null mutants. When such cells are exposed to genotoxic stress, Pds1/securin is stabilized in a spindle assembly checkpoint (SAC) dependent manner. Disruption of the SAC and the S phase checkpoint together, allows chromosome segregation in the presence of DNA damage or replication stress. Our results place the SAC as a part of the DDR, which appears to count on different, independent control layers to preserve genomic integrity when chromosome replication is challenged.
authors.affiliation: Biophysics Unit, School of Medicine, and Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, 08193, Catalonia, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Palou
authors.affiliation: Biophysics Unit, School of Medicine, and Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, 08193, Catalonia, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Palou
authors.affiliation: Biophysics Unit, School of Medicine, and Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, 08193, Catalonia, Spain. davidg.quintana@uab.cat.
authors.forename: David G
authors.initials: DG
authors.lastname: Quintana
mesh_terms: D000705:Anaphase / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics; D004249:DNA Damage; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D064249:Securin / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D047908:Intracellular Signaling Peptides and Proteins; C578004:PDS1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D064249:Securin; D064447:Checkpoint Kinase 2; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; D016203:CDC2 Protein Kinase; C067022:RAD53 protein, S cerevisiae
keywords: Chromosome segregation; Cyclin Dependent Kinase (Cdk1); DNA damage response (DDR); Genomic instability; S Phase checkpoint; Spindle assembly checkpoint (SAC)