The histone H3K36me3 mark regulates transcription elongation, pre-mRNA splicing, DNA methylation, and DNA damage repair. However, knowledge of the regulation of the enzyme SETD2, which deposits this functionally important mark, is very limited. Here we show that the poorly characterized N-terminal region of SETD2 plays a determining role in regulating the stability of SETD2. This stretch of 1-1403 amino acids contributes to the robust degradation of SETD2 by the proteasome. Besides, the SETD2 protein is aggregate-prone and forms insoluble bodies in nuclei especially upon proteasome inhibition. Removal of the N-terminal segment results in the stabilization of SETD2 and leads to a marked increase in global H3K36me3 which, uncharacteristically, happens in a Pol II-independent manner. Thus, the regulation of SETD2 levels through proteasomal mediated decay is important to maintain the fidelity of H3K36me3 deposition.

中文翻译：

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SETD2稳定性的调节对于H3K36me3沉积的保真度很重要

组蛋白H3K36me3标记调节转录伸长，mRNA剪接前，DNA甲基化和DNA损伤修复。但是，关于沉积该功能重要标记的酶SETD2的调控的知识非常有限。在这里我们表明，SETD2的N末端区域表征不佳，在调节SETD2的稳定性中起决定性作用。1-1403个氨基酸的延伸有助于蛋白酶体对SETD2的强烈降解。此外，SETD2蛋白是易于聚集的并且在细胞核中形成不溶体，特别是在蛋白酶体抑制时。N末端片段的删除导致SETD2的稳定化，并导致整体H3K36me3的显着增加，这通常以与Pol II无关的方式发生。从而，