H2A.Z-Dependent Regulation of Cohesin Dynamics on Chromosome Arms

Abstract

Structural maintenance of chromosomes (SMC) complexes and DNA topoisomerases are major determinants of chromosome structure and dynamics. The cohesin complex embraces sister chromatids throughout interphase, but during mitosis most cohesin is stripped from chromosome arms by early prophase, while the remaining cohesin at kinetochores is cleaved at anaphase. This two-step removal of cohesin is required for sister chromatids to separate. The cohesin-related Smc5/6 complex has been studied mostly as a determinant of DNA repair via homologous recombination. However, chromosome segregation fails in Smc5/6 null mutants or cells treated with small interfering RNAs. This also occurs in Smc5/6 hypomorphs in the fission yeast Schizosaccharomyces pombe following genotoxic and replication stress, or topoisomerase II dysfunction, and these mitotic defects are due to the postanaphase retention of cohesin on chromosome arms. Here we show that mitotic and repair roles for Smc5/6 are genetically separable in S. pombe. Further, we identified the histone variant H2A.Z as a critical factor to modulate cohesin dynamics, and cells lacking H2A.Z suppress the mitotic defects conferred by Smc5/6 dysfunction. Together, H2A.Z and the SMC complexes ensure genome integrity through accurate chromosome segregation.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00193-14.

ACKNOWLEDGMENTS

This work was supported by NIH NIGMS grant GM088162.

We are grateful to Michael Keogh, Antony Carr, Patrick Varga-Weisz, Rohinton Kamakaka, Johanne Murray, and Nancy Walworth for provision of strains, to the Mount Sinai Genomics Core facility for genomic sequence generation, and to Lekhana Bhandary for assistance with the early part of this study. We also acknowledge Nagma Shah for assistance with preparation of Fig. 4B.