Epigenetic Inactivation and Subsequent Heterochromatinization of a Centromere Stabilize Dicentric Chromosomes
Epigenetic Inactivation and Subsequent Heterochromatinization of a Centromere Stabilize Dicentric Chromosomes
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DOI：
10.1016/j.cub.2012.02.062
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发表时间：
2012-04-24
期刊：
影响因子：
9.2
通讯作者：
Saitoh, Shigeaki
中科院分区：
文献类型：
--
作者：
Sato, Hiroshi;Masuda, Fumie;Saitoh, Shigeaki
背景：着丝粒是一种多蛋白质复合体，在染色体的着丝粒上形成，在有丝分裂和减数分裂过程中将染色体与纺锤体连接起来。大多数真核生物，除了全着丝粒物种外，每条染色体都有一个不同的着丝粒，而在一条染色体上存在多个着丝粒被预测会导致该染色体的断裂和/或丢失。然而，已经报道了一些稳定维持的非罗伯逊易位染色体，这表明过量的着丝粒被一种尚不确定的机制灭活。结果：我们通过在分裂酵母中融合两条染色体来产生含有两条着丝粒的双着丝粒染色体。尽管大多数含有人工双着丝粒染色体的细胞以依赖于DNA结构检查点基因的方式以拉长的细胞形态被阻止，但部分细胞通过将双着丝粒染色体转化为稳定的功能单着丝粒染色体而存活下来；着丝粒要么是表观遗传失活的，要么是DNA重排的。损害着丝粒形成的突变增加了表观遗传着丝粒失活的频率。异染色质或组蛋白脱乙酰酶缺陷型染色体中的着丝粒被异染色质占据，常被重新激活。结论：多着丝粒染色体是由着丝粒解体启动的表观遗传着丝粒失活所稳定的。随之而来的异染色化和组蛋白去乙酰化从着丝粒周围重复序列扩展到中心区域，阻止了失活着丝粒的重新激活。
Background: The kinetochore is a multiprotein complex that forms on a chromosomal locus designated as the centromere, which links the chromosome to the spindle during mitosis and meiosis. Most eukaryotes, with the exception of holocentric species, have a single distinct centromere per chromosome, and the presence of multiple centromeres on a single chromosome is predicted to cause breakage and/or loss of that chromosome. However, some stably maintained non-Robertsonian translocated chromosomes have been reported, suggesting that the excessive centromeres are inactivated by an as yet undetermined mechanism.Results: We have developed systems to generate dicentric chromosomes containing two centromeres by fusing two chromosomes in fission yeast. Although the majority of cells harboring the artificial dicentric chromosome are arrested with elongated cell morphology in a manner dependent on the DNA structure checkpoint genes, a portion of the cells survive by converting the dicentric chromosome into a stable functional monocentric chromosome; either centromere was inactivated epigenetically or by DNA rearrangement. Mutations compromising kinetochore formation increased the frequency of epigenetic centromere inactivation. The inactivated centromere is occupied by heterochromatin and frequently reactivated in heterochromatin- or histone deacetylase-deficient mutants.Conclusions: Chromosomes with multiple centromeres are stabilized by epigenetic centromere inactivation, which is initiated by kinetochore disassembly. Consequent hetero-chromatinization and histone deacetylation expanding from pericentric repeats to the central domain prevent reactivation of the inactivated centromere.