title: Cohesion fatigue induces chromatid separation in cells delayed at metaphase.
abstract: BACKGROUND
  Chromosome instability is thought to be a major contributor to cancer malignancy and birth defects. For balanced chromosome segregation in mitosis, kinetochores on sister chromatids bind and pull on microtubules emanating from opposite spindle poles. This tension contributes to the correction of improper kinetochore attachments and is opposed by the cohesin complex that holds the sister chromatids together. Normally, within minutes of alignment at the metaphase plate, chromatid cohesion is released, allowing each cohort of chromatids to move synchronously to opposite poles in anaphase, an event closely coordinated with mitotic exit.
  
  
  RESULTS
  Here we show that during experimentally induced metaphase delay, spindle pulling forces can cause asynchronous chromatid separation, a phenomenon we term "cohesion fatigue." Cohesion fatigue is not blocked by inhibition of Plk1, a kinase essential for the "prophase pathway" of cohesin release from chromosomes, or by depletion of separase, the protease that normally drives chromatid separation at anaphase. Cohesion fatigue is inhibited by drug-induced depolymerization of mitotic spindle microtubules and by experimentally increasing the levels of cohesin on mitotic chromosomes. In cells undergoing cohesion fatigue, cohesin proteins remain associated with the separated chromatids.
  
  
  CONCLUSIONS
  In cells arrested at metaphase, pulling forces originating from kinetochore-microtubule interactions can, with time, rupture normal sister chromatid cohesion. This cohesion fatigue, resulting in unscheduled chromatid separation in cells delayed at metaphase, constitutes a previously overlooked source for chromosome instability in mitosis and meiosis.
authors.affiliation: Program in Cell Cycle and Cancer Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Daum
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Potapova
authors.forename: Sushama
authors.initials: S
authors.lastname: Sivakumar
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Daniel
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Flynn
authors.forename: Susannah
authors.initials: S
authors.lastname: Rankin
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Gorbsky
mesh_terms: D018797:Cell Cycle Proteins / Q000502:physiology*; D002842:Chromatids; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008677:Metaphase; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000097722:Cohesins