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Molecular and Cellular Biology, August 2009, p. 4363-4375, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00377-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Smc5-Smc6-Dependent Removal of Cohesin from Mitotic Chromosomes {triangledown}

Emily A. Outwin,1 Anja Irmisch,2 Johanne M. Murray,2 and Matthew J. O'Connell1*

Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York,1 Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, United Kingdom2

Received 24 March 2009/ Returned for modification 14 May 2009/ Accepted 3 June 2009

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.

* Corresponding author. Mailing address: Department of Oncological Sciences, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York, NY 10029. Phone: (212) 659-5468. Fax: (212) 987-2240. E-mail: matthew.oconnell{at}mssm.edu

{triangledown} Published ahead of print on 15 June 2009.

Molecular and Cellular Biology, August 2009, p. 4363-4375, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00377-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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