Histone H3 Lys4 (H3K4)甲基化由组蛋白-赖氨酸 N-甲基转移酶2（KMT2）蛋白家族催化，其成员对基因表达控制至关重要。在脊椎动物中，KMT2的功能是在大型多亚基复合物中进行的，这些复合物被称为COMPASS或COMPASS-like复合物（与Set1相关的蛋白质复合物）。这些复合物的活动对于适当的发育至关重要，并且其功能上的突变缺陷经常在人类肿瘤中发现。此外，KMT2基因的遗传性或新发生突变是神经发育障碍如Kabuki和Kleefstra综合征等的病因因素之一。 KMT2s的经典作用是催化H3K4甲基化，这会导致一个允许基因表达的染色质环境。然而，本文所述的当前研究发现表明这些酶也可以调节不依赖于甲基化的过程：KMT2s的非催化功能包括DNA损伤应答、细胞分裂和代谢活动。此外，这些酶还可能甲基化非组蛋白底物，并在DNA损伤应答中发挥甲基化依赖性功能。在本文中，我们总结了KMT2复合物在各种细胞过程中的新型非经典活动。这些发现可能对理解这些甲基转移酶在发育过程、疾病和表观遗传学靶向治疗策略方面的功能具有至关重要的意义。版权所有©2022 The Authors。由Elsevier BV出版。保留所有权利。

Histone H3 Lys4 (H3K4) methylation is catalyzed by the Histone-Lysine N-Methyltransferase 2 (KMT2) protein family, and its members are required for gene expression control. In vertebrates, the KMT2s function in large multisubunit complexes known as COMPASS or COMPASS-like complexes (COMplex of Proteins ASsociated with Set1). The activity of these complexes is critical for proper development, and mutation-induced defects in their functioning have frequently been found in human cancers. Moreover, inherited or de novo mutations in KMT2 genes are among the etiological factors in neurodevelopmental disorders such as Kabuki and Kleefstra syndromes. The canonical role of KMT2s is to catalyze H3K4 methylation, which results in a permissive chromatin environment that drives gene expression. However, current findings described in this review demonstrate that these enzymes can regulate processes that are not dependent on methylation: noncatalytic functions of KMT2s include DNA damage response, cell division, and metabolic activities. Moreover, these enzymes may also methylate non-histone substrates and play a methylation-dependent function in the DNA damage response. In this review, we present an overview of the new, noncanonical activities of KMT2 complexes in a variety of cellular processes. These discoveries may have crucial implications for understanding the functions of these methyltransferases in developmental processes, disease, and epigenome-targeting therapeutic strategies in the future.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.