Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition
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pigenetics & Chromatin Open Access
RESEARCH
Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition Saikat Bhattacharya and Jerry L. Workman*
Abstract Background: 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. Results: 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. Conclusion: The 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. Keywords: Chromatin, Proteasome, Histone, Methylation, Aggregation Background The N-terminal tails of histones protrude from the nucleosome and are hotspots for the occurrence of a variety of post-translational modifications (PTMs) that play key roles in regulating epigenetic processes. H3K36me3 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]. In mammalian cells, it is involved in the recruitment of DNA repair machinery, in splicing and also, in establishing DNA methylation patterns by acting as a binding site for the enzyme DNMT3a [2–6]. Recent reports have emphasized the tumor-suppressive role of H3K36me3 in renal cancer especially, where the gene coding for the SETD2 histone methyltransferase is often deleted or mutated [7–9].
*Correspondence: [email protected] Stowers Institute for Medical Research, Kansas City, MO 64110, USA
In yeast, the SET domain-containing protein Set2 (ySet2) is the sole H3K36 methyltransferase [10]. ySet2 interacts with the large subunit of the RNA polymerase II, Rpb1, through its SRI (Set2–Rpb1 Interaction) domain, and co-transcriptionally deposits H3K36me3 [11]. The deletion of the SRI domain from ySet2 abolishes both the Set2–RNA Pol II interaction and H3K36me3 methylation in yeast [12]. H3K36 methylation is a highly conserved histone mark and Set2 homologs are found in more complex eukaryotes [13]. These homologs share the conserved features like the AWS (associated with SET), SET [Su(var)3–9, Enhancer-of-zeste and Trithorax] and PostSET domains that are required for the catalytic activity of the enzyme, and also, the protein–protein interaction domains such as the WW and the SRI. Notably, the mammalian homolog, S
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