During mitosis, sister chromatids attach to microtubules from opposite poles, called biorientation. Sister chromatid cohesion resists microtubule forces, generating tension, which provides the signal that biorientation has occurred. How tension silences the surveillance pathways that prevent cell cycle progression and correct erroneous kinetochore–microtubule attachments remains unclear. Here we show that SUMOylation dampens error correction to allow stable sister kinetochore biorientation and timely anaphase onset. The Siz1/Siz2 SUMO ligases modify the pericentromere-localized shugoshin (Sgo1) protein before its tension-dependent release from chromatin. Sgo1 SUMOylation reduces its binding to protein phosphatase 2A (PP2A), and weakening of this interaction is important for stable biorientation. Unstable biorientation in SUMO-deficient cells is associated with persistence of the chromosome passenger complex (CPC) at centromeres, and SUMOylation of CPC subunit Bir1 also contributes to timely anaphase onset. We propose that SUMOylation acts in a combinatorial manner to facilitate dismantling of the error correction machinery within pericentromeres and thereby sharpen the metaphase–anaphase transition.
1The accurate segregation of chromosomes during mitosis relies on the attachment of 2 sister chromatids to microtubules from opposite poles, called biorientation. Sister 3 chromatid cohesion resists microtubule forces, generating tension which provides the 4 signal that biorientation has occurred. How tension silences the surveillance pathways 5 that prevent cell cycle progression and correct erroneous kinetochore-microtubule 6 remains unclear. Here we identify SUMOylation as a mechanism that promotes 7 anaphase onset upon biorientation. SUMO ligases modify the tension-sensing 8 pericentromere-localized chromatin protein, shugoshin, to stabilize bioriented sister 9 kinetochore-microtubule attachments. In the absence of SUMOylation, Aurora B 10 kinase removal from kinetochores is delayed. Shugoshin SUMOylation prevents its 11 binding to protein phosphatase 2A (PP2A) and release of this interaction is important 12 for stabilizing sister kinetochore biorientation. We propose that SUMOylation 13 modulates the kinase-phosphatase balance within pericentromeres to inactivate the 14 error correction machinery, thereby allowing anaphase entry in response to 15 biorientation. 16 biorientation has occurred is the tension-dependent removal of Sgo1 from the 51 pericentromere during metaphase, resulting in the delocalization of its effectors, 52 PP2A-Rts1, condensin and the CPC [8,14]. Upon anaphase I onset, Sgo1 is 53 ubiquitinated and degraded by APC/C-Cdc20 [14,15]. Similarly, human shugoshin is 54 degraded in anaphase as a result of APC/C-Cdc20 activity [16]. Shugoshin can be 55 stabilized by mutation of its APC-Cdc20-dependent destruction sequence in both 56 yeast and human cells, however, this does not impair the metaphase-anaphase 57 transition [13,14,17]. Nevertheless, there is evidence that Sgo1 inactivation is 58 important, since SGO1 overexpression results in a pronounced metaphase delay and a 59 block to cohesin cleavage [18]. Since the Sgo1-induced metaphase delay is abrogated 60 by deletion of BUB1, it is likely that Sgo1 must be localized at the pericentromere to 61 prevent anaphase onset [18]. Accordingly, we showed that Sgo1 and its associated 62 proteins are released from centromeres upon sister chromatid biorientation and 63 tension [8]. Potentially, the temporal separation between Sgo1 removal from each 64 pericentromere and its later degradation could ensure the reversibility of the 65 mechanism that monitors biorientation right up until the moment that the commitment 66 to anaphase is made. However, this model poses a conundrum: with the initiation of 67 cohesin cleavage at anaphase onset, tension between sister kinetochores is lost, which 68 could lead to re-activation of the error correction and biorientation pathways. What is 69 more, it was unclear whether Sgo1-associated PP2A-Rts1 and CPC depart from 70 centromeres simply by interacting with Sgo1, or by a more sophisticated mechanism 71 involving finely orchestrated interplay between kinase and phosphatase activities. 72Here, we identify Sgo1 SUMOyla...
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