小柯机器人

相分离指导基因体核小体泛素化
2020-03-13 13:18

近日,奥地利维也纳医科大学Alwin Köhler及其团队发现,相分离指导基因体核小体泛素化。相关论文于2020年3月11日在线发表于国际学术期刊《自然》。

据研究人员介绍,保守的酵母E3泛素连接酶Bre1及其伴侣E2泛素结合酶Rad6在转录周期中对不同基因体中的单泛素化组蛋白H2B。尽管从理论上讲,进行性泛素化来源于与RNA聚合酶II一起滑动的Bre1和Rad6,但是在不同基因核小体上的H2B泛素化机制仍不清楚。

研究人员发现,液-液相分离可能是潜在机理。生化重建显示,Bre1与支架蛋白Lge1结合,该蛋白具有通过多价相互作用进行相分离的固有无序区域。因此,这些聚集物包含被Bre1外部催化壳包裹的Lge1核。这种分层的液体吸收Rad6和核小体底物,从而加速H2B的泛素化。在体内,Lge1的聚集物形成区域是在+1核小体之外的基因体中泛素化H2B所必需的。
 
这些数据表明,组蛋白修饰酶的分层聚集物产生了染色质相关的“反应室”,并沿基因体增强了催化活性。人体细胞可能发生相同过程,并在受损时引起神经系统疾病。
 
附:英文原文
 
Title: Phase separation directs ubiquitination of gene-body nucleosomes

Author: Laura D. Gallego, Maren Schneider, Chitvan Mittal, Anete Romanauska, Ricardo M. Gudino Carrillo, Tobias Schubert, B. Franklin Pugh, Alwin Khler

Issue&Volume: 2020-03-11

Abstract: The conserved yeast E3 ubiquitin ligase Bre1 and its partner, the E2 ubiquitin-conjugating enzyme Rad6, monoubiquitinate histone H2B across gene bodies during the transcription cycle1. Although processive ubiquitination might—in principle—arise from Bre1 and Rad6 travelling with RNA polymerase II2, the mechanism of H2B ubiquitination across genic nucleosomes remains unclear. Here we implicate liquid–liquid phase separation3 as the underlying mechanism. Biochemical reconstitution shows that Bre1 binds the scaffold protein Lge1, which possesses an intrinsically disordered region that phase-separates via multivalent interactions. The resulting condensates comprise a core of Lge1 encapsulated by an outer catalytic shell of Bre1. This layered liquid recruits Rad6 and the nucleosomal substrate, which accelerates the ubiquitination of H2B. In vivo, the condensate-forming region of Lge1 is required to ubiquitinate H2B in gene bodies beyond the +1 nucleosome. Our data suggest that layered condensates of histone-modifying enzymes generate chromatin-associated ‘reaction chambers’, with augmented catalytic activity along gene bodies. Equivalent processes may occur in human cells, and cause neurological disease when impaired.

DOI: 10.1038/s41586-020-2097-z

Source: https://www.nature.com/articles/s41586-020-2097-z

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

分享到:

0