Yamagishi Yuya, Sakuno Takeshi, Shimura Mari, Watanabe Yoshinori
Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Tokyo 113-0032, Japan.
Nature. 2008 Sep 11;455(7210):251-5. doi: 10.1038/nature07217.
The centromere of a chromosome is composed mainly of two domains, a kinetochore assembling core centromere and peri-centromeric heterochromatin regions. The crucial role of centromeric heterochromatin is still unknown, because even in simpler unicellular organisms such as the fission yeast Schizosaccharomyces pombe, the heterochromatin protein Swi6 (HP1 homologue) has several functions at centromeres, including silencing gene expression and recombination, enriching cohesin, promoting kinetochore assembly, and, ultimately, preventing erroneous microtubule attachment to the kinetochores. Here we show that the requirement of heterochromatin for mitotic chromosome segregation is largely replaced by forcibly enriching cohesin at centromeres in fission yeast. However, this enrichment of cohesin is not sufficient to replace the meiotic requirement for heterochromatin. We find that the heterochromatin protein Swi6 associates directly with meiosis-specific shugoshin Sgo1, a protector of cohesin at centromeres. A point mutation of Sgo1 (V242E), which abolishes the interaction with Swi6, impairs the centromeric localization and function of Sgo1. The forced centromeric localization of Sgo1 restores proper meiotic chromosome segregation in swi6 cells. We also show that the direct link between HP1 and shugoshin is conserved in human cells. Taken together, our findings suggest that the recruitment of shugoshin is the important primary role for centromeric heterochromatin in ensuring eukaryotic chromosome segregation.
染色体的着丝粒主要由两个结构域组成，即组装动粒的核心着丝粒和着丝粒周围的异染色质区域。着丝粒异染色质的关键作用仍不清楚，因为即使在诸如裂殖酵母（Schizosaccharomyces pombe）这种较为简单的单细胞生物中，异染色质蛋白Swi6（HP1同源物）在着丝粒处也具有多种功能，包括沉默基因表达和重组、富集黏连蛋白、促进动粒组装，以及最终防止微管错误地附着到动粒上。在此，我们表明，在裂殖酵母中，通过在着丝粒处强行富集黏连蛋白，很大程度上取代了有丝分裂染色体分离过程中对异染色质的需求。然而，这种黏连蛋白的富集不足以取代减数分裂过程中对异染色质的需求。我们发现，异染色质蛋白Swi6直接与减数分裂特异性的守护蛋白Sgo1相互作用，Sgo1是着丝粒处黏连蛋白的保护因子。Sgo1的一个点突变（V242E）消除了与Swi6的相互作用，损害了Sgo1在着丝粒处的定位和功能。在swi6细胞中，Sgo1在着丝粒处的强制定位恢复了减数分裂染色体的正常分离。我们还表明，HP1与守护蛋白之间的直接联系在人类细胞中是保守的。综上所述，我们的研究结果表明，招募守护蛋白是着丝粒异染色质在确保真核生物染色体分离中重要的首要作用。
