Abstract
BackgroundThe 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.ResultsHere, 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.ConclusionThe functionally uncharacterized N-terminal segment of SETD2 regulates its half-life to maintain the requisite cellular amount of the protein. The absence of SETD2 proteolysis results in a Pol II-independent H3K36me3 deposition and protein aggregation.
Highlights
The histone H3K36me3 mark regulates transcription elongation, pre-mRNA splicing, DNA methylation, and DNA damage repair
To investigate whether autophagy plays a role in SETD2 turn-over, 293T cells expressing GFP-SETD2 full-length SETD2 (FL) were treated with increasing concentration of the lysosome inhibitor, chloroquine
We reveal that the absence of SETD2 proteolysis results in a Pol II-independent H3K36me3 deposition and protein aggregation
Summary
The histone H3K36me mark regulates transcription elongation, pre-mRNA splicing, DNA methylation, and DNA damage repair. H3K36me is one such important functionally characterized PTM In yeast, this mark suppresses cryptic transcription from within the coding region of genes by preventing histone exchange [1]. This mark suppresses cryptic transcription from within the coding region of genes by preventing histone exchange [1] In mammalian cells, it is involved in the recruitment of DNA repair machinery, in splicing and in establishing DNA methylation patterns by acting as a binding site for the enzyme DNMT3a [2,3,4,5,6]. The mammalian homolog, SETD2, has a long N-terminal segment that is not present in ySet2 The function of this region has remained obscure [13, 14]
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