Division of Biological Sciences, Molecular Biology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA 92103.
Mol Biol Cell. 2018 Sep 1;29(18):2201-2212. doi: 10.1091/mbc.E17-12-0701. Epub 2018 Jul 11.
Multiple interdependent mechanisms ensure faithful segregation of chromosomes during cell division. Among these, the spindle assembly checkpoint monitors attachment of spindle microtubules to the centromere of each chromosome, whereas the tension-sensing checkpoint monitors the opposing forces between sister chromatid centromeres for proper biorientation. We report here a new function for the deeply conserved Gcn5 acetyltransferase in the centromeric localization of Rts1, a key player in the tension-sensing checkpoint. Rts1 is a regulatory component of protein phopshatase 2A, a near universal phosphatase complex, which is recruited to centromeres by the Shugoshin (Sgo) checkpoint component under low-tension conditions to maintain sister chromatid cohesion. We report that loss of Gcn5 disrupts centromeric localization of Rts1. Increased RTS1 dosage robustly suppresses gcn5∆ cell cycle and chromosome segregation defects, including restoration of Rts1 to centromeres. Sgo1's Rts1-binding function also plays a key role in RTS1 dosage suppression of gcn5∆ phenotypes. Notably, we have identified residues of the centromere histone H3 variant Cse4 that function in these chromosome segregation-related roles of RTS1. Together, these findings expand the understanding of the mechanistic roles of Gcn5 and Cse4 in chromosome segregation.
在细胞分裂过程中，多种相互依赖的机制可确保染色体的正确分离。其中，纺锤体装配检查点监测纺锤体微管与每条染色体着丝粒的附着，而张力感应检查点则监测姐妹染色单体着丝粒之间的反向力，以确保正确的同源定向。我们在此报告了高度保守的 Gcn5 乙酰转移酶在 Rts1 着丝粒定位中的一个新功能，Rts1 是张力感应检查点的关键成员。Rts1 是蛋白磷酸酶 2A 的一个调节成分，后者是一种近普遍存在的磷酸酶复合物，在低张力条件下，通过 Shugoshin（Sgo）检查点成分被招募到着丝粒，以维持姐妹染色单体的黏合。我们报告说，Gcn5 的缺失会破坏 Rts1 的着丝粒定位。增加 RTS1 的剂量可显著抑制 gcn5∆ 细胞周期和染色体分离缺陷，包括将 Rts1 恢复到着丝粒。Sgo1 的 Rts1 结合功能在 RTS1 剂量抑制 gcn5∆ 表型方面也起着关键作用。值得注意的是，我们已经确定了着丝粒组蛋白 H3 变体 Cse4 的一些残基，这些残基在 RTS1 的这些染色体分离相关功能中发挥作用。总之，这些发现扩展了对 Gcn5 和 Cse4 在染色体分离中的机制作用的理解。
