DNA damage checkpoint maintains CDH1 in an active state to inhibit anaphase progression.
DNA damage checkpoint prevents segregation of damaged chromosomes by imposing cell-cycle arrest. In budding yeast, Mec1, Chk1, and Rad53 (homologous to human ATM/ATR, Chk1, and Chk2 kinases, respectively) are among the main effectors of this pathway. The DNA damage checkpoint is thought to inhibit chromosome segregation by preventing separase-mediated cleavage of cohesins. Here, we describe a regulatory network that prevents segregation of damaged chromosomes by restricting spindle elongation and acts in parallel with inhibition of cohesin cleavage. This control circuit involves Rad53, polo kinase, the anaphase-promoting complex activator Cdh1, and the bimC kinesin family proteins Cin8 and Kip1. The inhibition of polo kinase by Rad53-dependent phosphorylation prevents it from inactivating Cdh1. As a result, Cdh1 remains in a partially active state and limits Cin8 and Kip1 accumulation, thereby restraining spindle elongation. Hence, the DNA damage checkpoint suppresses both cohesin cleavage and spindle elongation to preserve chromosome stability.
Zhang
Tao
T
Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research) 61, Biopolis Drive, Proteos, Singapore 138673.
Nirantar
Saurabh
S
Lim
Hong Hwa
HH
Sinha
Indrajit
I
Surana
Uttam
U
D000705:Anaphase / Q000502:physiology*; D015153:Blotting, Western; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D064447:Checkpoint Kinase 2; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation; D004249:DNA Damage; D047468:Immunoprecipitation; D016547:Kinesins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D008941:Spindle Apparatus; D000097722:Cohesins
D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D002868:Chromosomal Proteins, Non-Histone; D016547:Kinesins; D008869:Microtubule-Associated Proteins; D020409:Molecular Motor Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D000097722:Cohesins; C577583:CDH1 protein, S cerevisiae; C075342:CIN8 protein, S cerevisiae; C431747:KIP1 protein, S cerevisiae; C081927:CDC5 protein, S cerevisiae; C067022:RAD53 protein, S cerevisiae