Nucleosome Assembly Proteins Get SET to Defeat the Guardian of Chromosome Cohesion

摘要

Cohesion between sister chromosomes is a critical mechanism used by eukaryotic cells to accomplish accurate chromosome segregation. As an analogy, imagine that you are struck one day by the (inexplicable) urge to segregate all your socks into two equal piles. The task will be much easier if you previously took the time to pair them up before tossing them in your dresser drawer. Similarly, keeping sister chromosomes together following DNA replication allows them to be efficiently sorted during cell division. In mitosis, cohesion at centromeres promotes bi-orientation of sister kinetochores by counteracting the pulling forces of microtubules emanating from opposite spindle poles. In meiosis, cohesion between chromosome arms facilitates segregation of recombined homologues during meiosis I by stabilizing the physical linkages (chiasmata) between them, and cohesion between centromeres is essential for accurate segregation of sisters in meiosis II [1] , [2] . A study by Moshkin and colleagues in this issue of PLOS Genetics [3] sheds new light on how these processes are regulated. Cohesion is brought about by ring-shaped cohesin complexes, which contain Smc1, Smc3, a kleisin (mainly Rad21/Scc1in mitosis and Rec8 in meiosis), and an associated SA/Scc3 subunit. In many animals, cohesion removal in mitosis occurs in two steps ( Figure 1A ). First, in the “prophase pathway,” phosphorylation of SA by kinases such as Polo triggers non-proteolytic removal of cohesin from chromosome arms. This promotes removal of the bulk of cohesin from the arms but, importantly, does not dissolve cohesion at centromeres. Later, once chromosomes are bi-oriented and the spindle checkpoint is satisfied, a proteolytic cohesion removal system is let loose: Separase cleaves the Rad21/Scc1 subunit of the remaining chromosome-bound cohesin, triggering chromosome separation and allowing anaphase [1] . In meiosis, removal of cohesin also occurs by a two-step process but, in contrast to mitosis, both steps require separase activity ( Figure 1B ). During meiosis I, separase cleaves Rec8 on the arms, leading to resolution of chiasmata and disjunction of homologues. Rec8 at centromeres is not cleaved until meiosis II, when the sisters separate, finally giving rise to a haploid gamete [1] , [2] . 10.1371/journal.pgen.1003829.g001 Figure 1 Models for regulation of chromosome cohesion in mitosis and meiosis. (A) In mitosis, cohesin (red rings) is phosphorylated and removed from chromosome arms by the “prophase pathway.” In this issue, Moshkin et al. provide evidence that Nap1 (blue) can displace PP2A (green) from cohesin to further promote cohesin release from chromosomes [3] . Cohesin at centromeres is protected by shugoshin-PP2A (yellow) until the metaphase–anaphase transition, when tension across bi-oriented sister kinetochores leads to the movement of shugoshin-PP2A away from cohesin at inner centromeres, allowing cohesin to be cleaved by separase [6] . It is not known if Nap1 has a role at this stage. (B) In meiosis I, phosphorylated cohesin linking sister chromosome arms is cleaved by separase, allowing recombined homologues to segregate. Cohesin at centromeres, however, is protected by shugoshin-PP2A, so that sister chromosomes remain together. In meiosis II, as in mitosis, the movement of shugoshin-PP2A away from inner centromeres on bi-oriented chromosomes allows cohesin between sisters to be phosphorylated and cleaved by separase [5] , [6] . Recent work from Chambon et al. and Qi et al. is consistent with the view that the Nap1-related protein SET (orange) relocates to inner centromeres in meiosis II to inhibit PP2A and provide an additional means to encourage cohesin phosphorylation and cleavage by separase [8] , [9] . Although the two-step removal systems in mitosis and meiosis are distinct, a common protein complex is implicated in protecting centromeric cohesion during the first step in both cases. Shugoshin/MEI-S332 family proteins collaborate with the phosphatase PP2A to prevent cohesin removal at centromeres [2] , [4] . In mitosis, shugoshin-PP2A complexes antagonize SA phosphorylation by mitotic kinases, preventing removal by the prophase pathway ( Figure 1A ). In meiosis, shugoshin-PP2A antagonizes phosphorylation of Rec8, preventing cleavage by separase ( Figure 1B ) [2] , [4] . A key question has been: What subsequently allows centromeric cohesion to be cleaved by separase in the second step? One proposed model is that, in response to tension across bi-oriented sister kinetochores, shugoshin-PP2A complexes move away from cohesin complexes at inner centromeres, making cohesin susceptible to removal by separase [5] , [6] . Newly published studies, described below, propose two additional (related) mechanisms that target PP2A to make cohesin sensitive to removal. Chambon et al. suggest that an inhibitor of PP2A, known as SET (or I2PP2A or TAF-I) [7] , is required to inactivate shugoshin-PP2A [8] . They reported, as in previous proteom