组蛋白H3K36位点甲基转移酶识别组蛋白底物的分子机制研究进展

Histone substrate recognition by histone H3K36 lysine methyltransferases

组蛋白H3第36位赖氨酸的甲基化修饰在染色质上含量丰富,与活跃转录以及DNA损伤修复等重要生理过程相关.H3K36位点可以被一甲基化、二甲基化和三甲基化3种形式修饰,目前已知的负责组蛋白H3K36三甲基化修饰的人源蛋白是SETD2,负责组蛋白H3K36二甲基化修饰的酶包含NSD1、NSD2和NSD3和ASH1L共4名成员.这些H3K36甲基转移酶都具有非常特异的H3K36位点选择性,因此,对调控体内H3K36甲基化修饰的水平和分布十分重要.此外,它们的表达异常与人类的多种疾病相关.因此,解析组蛋白H3K36甲基转移酶识别并修饰组蛋白底物的分子机制,对揭示这些酶参与的表观遗传调控机制及其在体内的生理功能都具有十分重要的意义.早期的研究使得人们对组蛋白H3K36甲基转移酶催化底物的机制有了较深入的认识,但是由于解析的修饰酶与底物复合物的结构较少,对这些酶特异识别组蛋白底物分子机制的认识尚有很多不足.近年来,随着冷冻电镜技术的应用,H3K36甲基转移酶与核小体底物的复合物结构相继取得了突破,极大地推进了人们对这些酶识别并催化组蛋白底物分子机制的认识.本文以这几个组蛋白H3K36甲基转移酶为主要目标,对其分子机制的最新进展进行介绍总结.

Histone H3 methylation at Lys36 is widespread on chromatin and is closely related to active transcription, DNA damage and repair. H3K36 can be methylated into mono-, di-and tri-methylation states.Currently,SETD2 is the only known human methyltransferase responsible for H3K36 tri-methylation,while NSD1,NSD2,NSD3 and ASH1L are responsible for H3K36 di-methylation. H3K36 methyltransferases are very specific for substrate histones, and thus are important for the distribution and methylation status of H3K36. In addition, their aberrant expressions are closely related to human diseases. Therefore,deciphering substrate recognition and catalysis mechanisms of these H3K36 methyltransferases are important to understand the epigenetic regulation mechanisms and the physiological roles of these enzymes in vivo. Previous studies on H3K36 methyltransferases greatly facilitated the understanding of their catalytic mechanisms. However,due to limited structural data on complexes of these enzymes with their bound substrates,questions related to their histone substrate recognition remain unanswered. With recent breakthroughs in cryo-EM technology,most complex structures of these H3K36 methyltransferases with their bound nucleosomal substrates are now solved,greatly advancing the understanding of their substrate recognition and catalysis mechanisms. This review article will focus on human H3K36 methyltransferases,with a particular emphasis on the molecular mechanisms of these enzymes.