SETD2是抑癌基因，编码蛋白是一种染色质调节酶，其通过组蛋白H3K36的位点特异性三甲基化发挥作用。它最初被认定为亨廷顿病发病机制中的一种酶，因此最初被命名为亨廷顿相互作用蛋白B（HYPB）。SETD2调节的H3K36组蛋白标记起到调节DNA错配修复的作用。因此，SETD2蛋白的失活可以导致增强的遗传不稳定性，无义和移码突变的富集以及最终的细胞致癌转化。重要的是，SETD2突变的肾肿瘤未能激活p53肿瘤抑制剂，从而为p53失活提供了另一导致DNA损伤修复中的缺陷。目前，已经在多种癌症类型中鉴定了SETD2的突变。

SETD2 encodes a chromatin modulating enzyme that functions by site specific trimethylation of histone H3K36. It was originally identified as a contributing enzyme in the pathogenesis of Huntington Disease and thus was initially named Huntington Interacting Protein B (HYPB). Histone methylation is a highly controlled biological process that regulates gene expression by altering the ability of RNA polymerase II to interact with DNA and thus initiate transcription. Additionally, the SETD2-regulated H3K36 histone mark has been shown to play a role in regulating DNA mismatch repair. This suggests that inactivation of this protein can lead to enhanced genetic instability, enrichment of nonsense and frameshift mutations and ultimately oncogenic transformation of cells. Importantly, SETD2-mutant renal tumors failed to activate the p53 tumor suppressor, thus providing an alternative pathway for the inactivation of p53 that leads to defects in DNA damage repair

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