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Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3-MutS{alpha} interaction [Genetics]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2018-09-18 , DOI: 10.1073/pnas.1806355115
Jun Fang 1, 2 , Yaping Huang 1, 2 , Guogen Mao 3 , Shuang Yang 1, 2 , Gadi Rennert 4 , Liya Gu 5 , Haitao Li 1, 2 , Guo-Min Li 3, 5
Affiliation  

Somatic mutations on glycine 34 of histone H3 (H3G34) cause pediatric cancers, but the underlying oncogenic mechanism remains unknown. We demonstrate that substituting H3G34 with arginine, valine, or aspartate (H3G34R/V/D), which converts the non-side chain glycine to a large side chain-containing residue, blocks H3 lysine 36 (H3K36) dimethylation and trimethylation by histone methyltransferases, including SETD2, an H3K36-specific trimethyltransferase. Our structural analysis reveals that the H3 “G33-G34” motif is recognized by a narrow substrate channel, and that H3G34/R/V/D mutations impair the catalytic activity of SETD2 due to steric clashes that impede optimal SETD2–H3K36 interaction. H3G34R/V/D mutations also block H3K36me3 from interacting with mismatch repair (MMR) protein MutSα, preventing the recruitment of the MMR machinery to chromatin. Cells harboring H3G34R/V/D mutations display a mutator phenotype similar to that observed in MMR-defective cells. Therefore, H3G34R/V/D mutations promote genome instability and tumorigenesis by inhibiting MMR activity.



中文翻译:

致癌的H3G34V / R / D突变可阻止H3K36甲基化和H3K36me3-MutS {alpha}相互作用[遗传学]

组蛋白H3(H3G34)的甘氨酸34上的体细胞突变引起儿童癌症,但潜在的致癌机制仍然未知。我们证明用精氨酸,缬氨酸或天冬氨酸(H3G34R / V / D)取代H3G34,可将非侧链甘氨酸转化为含侧链的较大残基,阻止H3赖氨酸36(H3K36)二甲基化和三甲基化的组蛋白甲基转移酶,包括H3K36特异性三甲基转移酶SETD2。我们的结构分析表明,H3“ G33-G34”基序可被狭窄的底物通道识别,并且由于空间碰撞而阻碍了SETD2-H3K36的最佳相互作用,H3G34 / R / V / D突变会损害SETD2的催化活性。H3G34R / V / D突变也阻止H3K36me3与错配修复(MMR)蛋白MutSα相互作用,从而阻止MMR机制募集到染色质。携带H3G34R / V / D突变的细胞表现出与在MMR缺陷细胞中观察到的相似的突变体表型。因此,H3G34R / V / D突变通过抑制MMR活性促进基因组不稳定性和肿瘤发生。

更新日期:2018-09-19
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