H3.3 G34W 癌组蛋白突变通过蛋白赖氨酸甲基转移酶 NSD1 增加 K36 甲基化。

The H3.3 G34W oncohistone mutation increases K36 methylation by the protein lysine methyltransferase NSD1.

机构信息

Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.

Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany; Biochemistry Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, Cairo, 11566, Egypt.

出版信息

Biochimie. 2022 Jul;198:86-91. doi: 10.1016/j.biochi.2022.03.007. Epub 2022 Mar 24.

DOI:10.1016/j.biochi.2022.03.007

PMID:35341929

Abstract

The H3.3 G34W mutation has been observed in 90% of the patients affected by giant cell tumor of bone (GCTB). It had been shown to reduce the activity of the SETD2 H3K36 protein lysine methyltransferase (PKMT) and lead to genome wide changes in epigenome modifications including a global reduction in DNA methylation. Here, we investigated the effect of the H3.3 G34W mutation on the activity of the H3K36me2 methyltransferase NSD1, because NSD1 is known to play an important role in the differentiation of chondrocytes and osteoblasts. Unexpectedly, we observed that H3.3 G34W has a gain-of-function effect and it stimulates K36 methylation by NSD1 by about 2.3-fold with peptide substrates and 6.3-fold with recombinant nucleosomal substrates. This effect is specific for NSD1, as NSD2 shows only a mild stimulation on G34W substrates. The potential downstream effects of the G34W induced hyperactivity of NSD1 on DNA methylation, H3K27me3, histone acetylation and splicing are discussed.

摘要

H3.3 G34W 突变已在 90%的骨巨细胞瘤 (GCTB) 患者中观察到。它已被证明降低 SETD2 H3K36 蛋白赖氨酸甲基转移酶 (PKMT) 的活性，并导致全基因组表观遗传修饰变化，包括 DNA 甲基化的整体减少。在这里，我们研究了 H3.3 G34W 突变对 H3K36me2 甲基转移酶 NSD1 活性的影响，因为 NSD1 已知在软骨细胞和成骨细胞分化中发挥重要作用。出乎意料的是，我们观察到 H3.3 G34W 具有功能获得效应，它通过肽底物刺激 NSD1 的 K36 甲基化约 2.3 倍，通过重组核小体底物刺激约 6.3 倍。这种效应是 NSD1 特异性的，因为 NSD2 对 G34W 底物仅显示出轻微的刺激。讨论了 G34W 诱导 NSD1 过度活跃对 DNA 甲基化、H3K27me3、组蛋白乙酰化和剪接的潜在下游影响。