Structure and function of the lysine methyltransferase SETD2 in cancer: From histones to cytoskeleton

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology Neoplasia Pub Date : 2024-11-25 DOI:10.1016/j.neo.2024.101090

Christina Michail, Fernando Rodrigues Lima, Mireille Viguier, Frédérique Deshayes

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Abstract

SETD2 is known to be the unique histone methyltransferase responsible for the trimethylation of the lysine 36 of histone H3 thus generating H3K36me3. This epigenetic mark is critical for transcriptional activation and elongation, DNA repair, mRNA splicing, and DNA methylation. Recurrent SETD2-inactivating mutations and altered H3K36me3 levels are found in cancer at high frequency and numerous studies indicate that SETD2 acts as a tumor suppressor. Recently, SETD2 was further shown to methylate non-histone proteins particularly the cytoskeletal proteins tubulin and actin with subsequent impacts on cytoskeleton structure, mitosis and cell migration.

Herein, we provide a review of the role of SETD2 in different cancers with special emphasis on the structural basis of the functions of this key lysine methyltransferase. Moreover, beyond the role of this enzyme in epigenetics and H3K36me3-dependent processes, we highlight the putative role of "non-epigenetic/H3K36me3" functions of SETD2 in cancer, particularly those involving the cytoskeleton.

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癌症中赖氨酸甲基转移酶 SETD2 的结构和功能：从组蛋白到细胞骨架

众所周知，SETD2 是一种独特的组蛋白甲基转移酶，负责对组蛋白 H3 的 36 号赖氨酸进行三甲基化，从而生成 H3K36me3。这种表观遗传标记对转录激活和延伸、DNA 修复、mRNA 剪接和 DNA 甲基化至关重要。在癌症中经常发现 SETD2 失活突变和 H3K36me3 水平的改变，大量研究表明 SETD2 是一种肿瘤抑制因子。最近，研究进一步表明 SETD2 可甲基化非组蛋白，尤其是细胞骨架蛋白微管蛋白和肌动蛋白，从而对细胞骨架结构、有丝分裂和细胞迁移产生影响。在此，我们对 SETD2 在不同癌症中的作用进行了综述，并特别强调了这一关键赖氨酸甲基转移酶功能的结构基础。此外，除了该酶在表观遗传学和H3K36me3依赖过程中的作用外，我们还强调了SETD2在癌症中的 "非表观遗传学/H3K36me3 "功能，尤其是涉及细胞骨架的功能。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.