SGO1C is a non-functional isoform of Shugoshin and can disrupt sister chromatid cohesion by interacting with PP2A–B56

Shugoshin (SGO1) plays a pivotal role in sister chromatid cohesion during mitosis by protecting the centromeric cohesin from mitotic kinases and WAPL. Mammalian cells contain at least 6 alternatively spliced isoforms of SGO1. The relationship between the canonical SGO1A with shorter isoforms including SGO1C remains obscure. Here we show that SGO1C was unable to replace the loss of SGO1A. Instead, expression of SGO1C alone induced aberrant mitosis similar to depletion of SGO1A, promoting premature sister chromatid separation, activation of the spindle-assembly checkpoint, and mitotic arrest. In disagreement with previously published data, we found that SGO1C localized to kinetochores. However, the ability to induce aberrant mitosis did not correlate with its kinetochore localization. SGO1C mutants that abolished binding to kinetochores still triggered premature sister chromatid separation. We provide evidence that SGO1C-mediated mitotic arrest involved the sequestering of PP2A–B56 pool. Accordingly, SGO1C mutants that abolished binding to PP2A localized to kinetochores but did not induce aberrant mitosis. These studies imply that the expression of SGO1C should be tightly regulated to prevent dominant-negative effects on SGO1A and genome instability.

守护素（Shugoshin, SGO1）通过保护着丝粒黏连素（centromeric cohesin）免受有丝分裂激酶（mitotic kinases）与WAPL的作用，在有丝分裂过程中对姐妹染色单体黏着（sister chromatid cohesion）发挥关键调控作用。哺乳动物细胞中至少存在6种SGO1的可变剪接异构体（alternatively spliced isoforms）。经典型SGO1A与包括SGO1C在内的较短异构体之间的功能关联仍不明确。本研究发现，SGO1C无法代偿SGO1A的功能缺失。相反，单独表达SGO1C可诱发与SGO1A缺失相似的异常有丝分裂，促进姐妹染色单体提前分离（premature sister chromatid separation）、激活纺锤体组装检验点（spindle-assembly checkpoint）并引发有丝分裂阻滞（mitotic arrest）。与此前已发表的研究结果相悖，我们发现SGO1C定位于动粒（kinetochores）。然而，其诱发异常有丝分裂的能力与其动粒定位并无关联：丧失动粒结合能力的SGO1C突变体仍可触发姐妹染色单体提前分离。我们的研究证据表明，SGO1C介导的有丝分裂阻滞涉及PP2A–B56复合物库的隔离。相应地，丧失PP2A结合能力的SGO1C突变体虽可定位于动粒，但无法诱发异常有丝分裂。本研究提示，需对SGO1C的表达进行严格调控，以避免其对SGO1A产生显性负效应（dominant-negative effects）并引发基因组不稳定性（genome instability）。