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研究揭示减数分裂DNA断裂的机制
2021-03-18 16:17

美国纪念斯隆·凯特琳癌症中心和霍华德·休斯医学院Scott Keeney、Corentin Claeys Bouuaert研究团队,探明了DNA诱导的染色质收缩是减数分裂DNA断裂的原因。这一研究成果在线发表在2021年3月17日出版的《自然》上。

研究人员通过对酿酒酵母RMM(Rec114、Mei4和Mer2)蛋白的分子表征(调控DNA双链断裂(DSB)基本组成部分)来探究DNA断裂过程中蛋白质的组装。Rec114–Mei4(2:1异源三聚体)或Mer2(含有卷曲螺旋的同四聚体)的每个亚复合物均单分散在溶液中,但它们独立地与DNA缩合成可逆的核蛋白簇,这类似于相分离系统。多价相互作用促进了这种缩合。减弱蛋白质-DNA相互作用的突变会强烈破坏体内缩合物的形成和DSB,因而这些过程高度相关。

在体外,缩合物融合到混合的RMM簇中,从而进一步招募Spo11复合物。这些数据显示了DSB如何在染色体上自组装以建立DSB活跃中心。研究人员猜测调节组分的招募和缩合物生物物理特性的调节是po11多层调控的来源。

据介绍,减数分裂过程中染色体的精确分离(其对生殖周期基因组稳定性至关重要)取决于Spo11蛋白诱导DSB引发的同源重组。DSBs的形成受到调控,并与大型染色体结构的精细化相关,但对执行和控制DNA断裂的蛋白质组装了解甚少。

附:英文原文

Title: DNA-driven condensation assembles the meiotic DNA break machinery

Author: Corentin Claeys Bouuaert, Stephen Pu, Juncheng Wang, Cdric Oger, Dima Daccache, Wei Xie, Dinshaw J. Patel, Scott Keeney

Issue&Volume: 2021-03-17

Abstract: The accurate segregation of chromosomes during meiosis—which is critical for genome stability across sexual cycles—relies on homologous recombination initiated by DNA double-strand breaks (DSBs) made by the Spo11 protein1,2. The formation of DSBs is regulated and tied to the elaboration of large-scale chromosome structures3,4,5, but the protein assemblies that execute and control DNA breakage are poorly understood. Here we address this through the molecular characterization of Saccharomyces cerevisiae RMM (Rec114, Mei4 and Mer2) proteins—essential, conserved components of the DSB machinery2. Each subcomplex of Rec114–Mei4 (a 2:1 heterotrimer) or Mer2 (a coiled-coil-containing homotetramer) is monodispersed in solution, but they independently condense with DNA into reversible nucleoprotein clusters that share properties with phase-separated systems. Multivalent interactions drive this condensation. Mutations that weaken protein–DNA interactions strongly disrupt both condensate formation and DSBs in vivo, and thus these processes are highly correlated. In vitro, condensates fuse into mixed RMM clusters that further recruit Spo11 complexes. Our data show how the DSB machinery self-assembles on chromosome axes to create centres of DSB activity. We propose that multilayered control of Spo11 arises from the recruitment of regulatory components and modulation of the biophysical properties of the condensates.

DOI: 10.1038/s41586-021-03374-w

Source: https://www.nature.com/articles/s41586-021-03374-w

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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