Smc5-Smc6-dependent removal of cohesin from mitotic chromosomes.
The function of the essential cohesin-related Smc5-Smc6 complex has remained elusive, though hypomorphic mutants have defects late in recombination, in checkpoint maintenance, and in chromosome segregation. Recombination and checkpoints are not essential for viability, and Smc5-Smc6-null mutants die in lethal mitoses. This suggests that the chromosome segregation defects may be the source of lethality in irradiated Smc5-Smc6 hypomorphs. We show that in smc6 mutants, following DNA damage in interphase, chromosome arm segregation fails due to an aberrant persistence of cohesin, which is normally removed by the Separase-independent pathway. This postanaphase persistence of cohesin is not dependent on DNA damage, since the synthetic lethality of smc6 hypomorphs with a topoisomerase II mutant, defective in mitotic chromosome structure, is also due to the retention of cohesin on undamaged chromosome arms. In both cases, Separase overexpression bypasses the defect and restores cell viability, showing that defective cohesin removal is a major determinant of the mitotic lethality of Smc5-Smc6 mutants.
Outwin
Emily A
EA
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Irmisch
Anja
A
Murray
Johanne M
JM
O'Connell
Matthew J
MJ
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation; D002875:Chromosomes / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D064247:Separase; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D010450:Endopeptidases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D029702:Schizosaccharomyces pombe Proteins; D064247:Separase; D000097722:Cohesins; C092957:Rad21 protein, S pombe; C486628:Smc5 protein, S pombe; C486630:smc6 protein, S pombe; C577987:ESPL1 protein, human