Escape from Mitotic Arrest: An Unexpected Connection Between Microtubule Dynamics and Epigenetic Regulation of Centromeric Chromatin in Schizosaccharomyces pombe.
Accurate chromosome segregation is necessary to ensure genomic integrity. Segregation depends on the proper functioning of the centromere, kinetochore, and mitotic spindle microtubules and is monitored by the spindle assembly checkpoint (SAC). In the fission yeast Schizosaccharomyces pombe, defects in Dis1, a microtubule-associated protein that influences microtubule dynamics, lead to mitotic arrest as a result of an active SAC and consequent failure to grow at low temperature. In a mutant dis1 background (dis1-288), loss of function of Msc1, a fission yeast homolog of the KDM5 family of proteins, suppresses the growth defect and promotes normal mitosis. Genetic analysis implicates a histone deacetylase (HDAC)-linked pathway in suppression because HDAC mutants clr6-1, clr3∆, and sir2∆, though not hos2∆, also promote normal mitosis in the dis1-288 mutant. Suppression of the dis phenotype through loss of msc1 function requires the spindle checkpoint protein Mad2 and is limited by the presence of the heterochromatin-associated HP1 protein homolog Swi6. We speculate that alterations in histone acetylation promote a centromeric chromatin environment that compensates for compromised dis1 function by allowing for successful kinetochore-microtubule interactions that can satisfy the SAC. In cells arrested in mitosis by mutation of dis1, loss of function of epigenetic determinants such as Msc1 or specific HDACs can promote cell survival. Because the KDM5 family of proteins has been implicated in human cancers, an appreciation of the potential role of this family of proteins in chromosome segregation is warranted.
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635.
Anuja A
http://orcid.org/0000-0003-2643-6307
AA
George
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635 Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903-2681 nancy.walworth@rutgers.edu.
Nancy C
http://orcid.org/0000-0001-5940-8236
NC
Walworth
D002503:Centromere; D002843:Chromatin / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D008870:Microtubules / Q000502:physiology*; D008938:Mitosis; D009154:Mutation; D012568:Schizosaccharomyces / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000502:physiology
D002843:Chromatin; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; C486643:Msc1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C094879:dis1 protein, S pombe; D006655:Histone Deacetylases
Dis1 (XMAP215, TOG1); Mad2; Msc1; PLU-1; RBP2; Rb; Swi6 (HP1 homolog); histone deacetylase (HDAC); lysine demethylase KDM5; thiabendazole; trichostatin