DNA damage checkpoint maintains CDH1 in an active state to inhibit anaphase progression

Dev Cell. 2009 Oct;17(4):541-51. doi: 10.1016/j.devcel.2009.09.006.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase / physiology*
  • Blotting, Western
  • Cdh1 Proteins
  • Cell Cycle Proteins / metabolism
  • Checkpoint Kinase 2
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation
  • DNA Damage*
  • Immunoprecipitation
  • Kinesin
  • Microtubule-Associated Proteins / metabolism
  • Molecular Motor Proteins / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Spindle Apparatus*

Substances

  • CDH1 protein, S cerevisiae
  • CIN8 protein, S cerevisiae
  • Cdh1 Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • KIP1 protein, S cerevisiae
  • Microtubule-Associated Proteins
  • Molecular Motor Proteins
  • Saccharomyces cerevisiae Proteins
  • cohesins
  • Protein Kinases
  • Checkpoint Kinase 2
  • Protein-Serine-Threonine Kinases
  • CDC5 protein, S cerevisiae
  • RAD53 protein, S cerevisiae
  • Kinesin