Functional interplay between cohesin and Smc5/6 complexes

Abstract

Chromosomes are subjected to massive re-engineering as they are replicated, transcribed, repaired, condensed and segregated into daughter cells. Among the engineers are three large protein complexes collectively known as the Structural Maintenance of Chromosomes (SMC) complexes: cohesin, condensin and Smc5/6. As their names suggest, cohesin controls sister chromatid cohesion, condensin controls chromosome condensation, and while precise functions for Smc5/6 have remained somewhat elusive, most reports have focused on the control of recombinational DNA repair. Here, we focus on cohesin and Smc5/6 function. It is becoming increasingly clear that the functional repertoires of these complexes is greater than sister chromatid cohesion and recombination. These SMC complexes are emerging as inter-related and cooperating factors that control chromosome dynamics throughout interphase. However, they also release their embrace of sister chromatids to enable their segregation at anaphase, resetting the dynamic cycle of SMC-chromosome interactions.

An acetyltransferase-independent function of Eso1 regulates centromere cohesion

“…The blockade to sister chromatid separation caused by the retention of existing arm cohesin complexes in smc6-74 cells after DNA damage or replication stress is also suppressed by eso1-H17 (Figures 5 and 6). Of note, centromeric cohesin and cohesion are unaffected in smc6-74 and other Smc5/6 mutants (Outwin et al , 2009; Tapia-Alveal et al , 2014a, b). Because acetyl-mimetic psm3-NN enhances the HU sensitivity of smc6-74 (Figure 7B), the suppressing effects of eso1-H17 are likely to be, at least in part, via Psm3 hypoacetylation.…”

“…Smc5/6 is required for the separase-independent prophase pathway of cohesin removal from chromosome arms; Smc5/6 genes are essential, but this defect can be induced in hypomorphs such as smc6-74 by DNA damage and replication stress (Outwin et al , 2009; Tapia-Alveal et al , 2014a, b). Although Smc5/6 does not mediate centromeric cohesin removal, we believed it was possible that Smc5/6 (as a cohesin regulator) and Eso1 might interact in the regulation of centromeric separation.…”

“…The function(s) of the third complex, Smc5/6, have remained enigmatic, but most studies have focused on recombinational repair of double-stranded DNA breaks and collapsed replication forks (Murray and Carr, 2008). However, the core Smc5/6 genes are essential for viability, with null mutants initiating but unable to complete chromosome segregation (Verkade et al , 1999; Harvey et al , 2004; Tapia-Alveal et al , 2014a). …”

“…This occurs spontaneously in null mutants and in hypomorphs after DNA damage or replication stress (Verkade et al , 1999; Harvey et al , 2004). The mitotic failure is due to the postanaphase retention of cohesin on chromosome arms but not centromeres (Outwin et al , 2009; Tapia-Alveal et al , 2014a, b), that is, a failure of the prophase pathway. Although the mechanism leading to cohesin retention is not yet clear, the mitotic defects can be overcome by ectopic expression of separase (Outwin et al , 2009) and the loss of the histone variant H2A.Z (Tapia-Alveal et al , 2014b); both of these scenarios significantly lower arm cohesin levels, although H2A.Z levels have little to no effect on centromeric cohesin.…”

“…A similar dependence on Smc5/6 for cohesin removal has been found in S. cerevisiae during meiosis (Copsey et al , 2013) but not during mitosis (Jeppsson et al , 2014), in which the prophase pathway does not function. Of note, the genomic locations of cohesin and Smc5/6 are largely overlapping (Pebernard et al , 2008; Jeppsson et al , 2014), and thus there is significant cross-talk between these related complexes (Tapia-Alveal et al , 2014a). …”