Functional Studies on Primary Tubular Epithelial Cells Indicate a Tumor Suppressor Role of SETD2 in Clear Cell Renal Cell Carcinoma

Li, Jun; Kluiver, Joost; Osinga, Jan; Westers, Helga; Werkhoven, Maaike B. van; Seelen, Marc A.; Sijmons, Rolf H.; Berg, Anke van den; Kok, Klaas

doi:10.1016/j.neo.2016.04.005

Cited by 24 publications

(25 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mouse mesenchymal progenitor cells (MPCs) that stably express either wildtype or K36M mutant H3.3 formed tumors after subcutaneous injection in immunocompro-mised mice (Lu et al 2016). In renal primary epithelial tubule cells, cells considered to be the progenitor for ccRCC, SETD2 knockdown resulted in continued proliferation well past the point at which these cells typically senesce (Li et al 2016). In models of MLL-rearranged leukemia, SETD2 loss is associated with increased colony formation, proliferation, and accelerated leukemia development after transplantation .…”

Section: Setd2 In Cancer Development and Therapeuticsmentioning

confidence: 99%

SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation

Fahey

Davis

2017

Cold Spring Harb Perspect Med

View full text Add to dashboard Cite

The H3 lysine 36 histone methyltransferase is mutated across a range of human cancers. Although other enzymes can mediate mono- and dimethylation, SETD2 is the exclusive trimethylase. SETD2 associates with the phosphorylated carboxy-terminal domain of RNA polymerase and modifies histones at actively transcribed genes. The functions associated with SETD2 are mediated through multiple effector proteins that bind trimethylated H3K36. These effectors directly mediate multiple chromatin-regulated processes, including RNA splicing, DNA damage repair, and DNA methylation. Although alterations in each of these processes have been associated with SETD2 loss, the relative role of each in the development of cancer is not fully understood. Critical vulnerabilities resulting from SETD2 loss may offer a strategy for potential therapeutics.

show abstract

Section: Setd2 In Cancer Development and Therapeuticsmentioning

confidence: 99%

SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation

Fahey

Davis

2017

Cold Spring Harb Perspect Med

View full text Add to dashboard Cite

show abstract

“…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][3] [4][5] [6]. Recent reports have emphasized the 3 tumor-suppressive role of H3K36me3 in renal cancer especially, where the gene coding for the SETD2 histone methyltransferase is often deleted or mutated [7][8] [9].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the regulation of SETD2 levels through intrinsically disordered region-facilitated proteolysis is important to maintain the fidelity of transcription and splicing related processes. gene coding for the SETD2 histone methyltransferase is often deleted or mutated )(Su et al, 2017)(Li et al, 2016.In yeast, the SET domain-containing protein Set2 (ySet2) is the sole H3K36 methyltransferase (Strahl et al, 2002). ySet2 interacts with the large subunit of the RNA polymerase II, Rpb1, through its SRI domain, and co-transcriptionally deposits H3K36me3 (Xiao et al, 2003).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition

Bhattacharya

Workman

2020

Preprint

View full text Add to dashboard Cite

The SET domain-containing protein SETD2 is the sole methyltransferase in mammals that can trimethylate histone H3 at lysine 36. H3K36me3 is known to be involved in transcription elongation, pre-mRNA splicing, DNA methylation, and DNA damage repair. However, knowledge of the regulation of the SETD2 enzyme itself is 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 acid residues which contains disordered regions, is targeted for degradation by the proteasome. In addition, the SETD2 protein is aggregate-prone and forms insoluble inclusion 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, can happen in an RNA Pol II-independent manner. The spurious H3K36me3 is deposited in a non-canonical distribution including reduced enrichment over gene bodies and exons. An increased SETD2 abundance leads to widespread changes in transcription and alternative splicing. Thus, the regulation of SETD2 levels through intrinsically disordered region-facilitated proteolysis is important to maintain the fidelity of transcription and splicing related processes. gene coding for the SETD2 histone methyltransferase is often deleted or mutated )(Su et al, 2017)(Li et al, 2016.In yeast, the SET domain-containing protein Set2 (ySet2) is the sole H3K36 methyltransferase (Strahl et al, 2002). ySet2 interacts with the large subunit of the RNA polymerase II, Rpb1, through its SRI domain, and co-transcriptionally deposits H3K36me3 (Xiao et al, 2003). The deletion of the SRI domain from ySet2 abolishes both the Set2-RNA Pol II interaction and H3K36me3 methylation in yeast (Suzuki et al, 2016). H3K36 methylation is a highly conserved histone mark and Set2 homologs are found in more complex eukaryotes (McDaniel & Strahl, 2017). These homologs share the conserved features like the AWS (associated with SET), SET [Su(var)3-9, Enhancer-of-zeste and Trithorax] and Post-SET domains that are required for the catalytic activity of the enzyme, and also, the protein-protein interaction regions such as the WW and SRI (Set2-Rpb1 Interaction) domains. However, there are differences in both the manner of H3K36me3 deposition in mammals as well as in the enzyme itself as compared to yeast. For instance, although SETD2 is the sole methyltransferase in mammals that can deposit the histone H3K36me3 mark, there are additional enzymes such as NSD1, NSD2, and ASH1L that can deposit H3K36me1 and me2 (Lucio-Eterovic et al, 2010)(Kuo et al, 2011)(Tanaka et al, 2007). Notably, SETD2 has a long N-terminal segment that is not present in ySet2. The function of this region has remained obscure (McDaniel & Strahl, 2017)(Hacker et al, 2016).Here we show that SETD2 is an inherently aggregate-prone protein and its N-terminal region regulates its half-life. This, in turn, is important for the fidelity of H3K36me3 ...

show abstract

“…Besides histone H3 methylation, SETD2 also has non-histone substrates such as tubulin 3 and STAT1 (Park et al 2016) (Chen et al 2017a). Consistent with its functionally important role, SETD2 deletion is embryonically lethal and mutations in SETD2 have been reported in many cancers, including CCRCC (Hu et al 2010) (Zhu et al 2014) (Duns et al 2010) (Al Sarakbi et al 2009) ) (Su et al 2017) (Li et al 2016). SETD2 depletion is clearly detrimental to cells.…”

Section: Introductionmentioning

confidence: 99%

The disordered regions of SETD2 govern H3K36me3 deposition by regulating its proteasome-mediated decay

Bhattacharya

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

SETD2 is the sole methyltransferase that tri-methylates histone H3 at lysine 36 in mammals. It has an extended N-terminal region which is absent in its yeast homolog Set2. The function of this poorly characterized region in regulating SETD2 stability has been reported. However, how this region regulates SETD2 half-life and the consequences of the cellular accumulation of SETD2 is unclear. Here we show that the SETD2 N-terminal region contains disordered regions and is targeted for degradation by the proteasome. The marked increase in global H3K36me3 that occurs on the removal of the N-terminal segment results in a non-canonical distribution including reduced enrichment over gene bodies and exons. An increased SETD2 abundance leads to widespread changes in transcription and alternative splicing. Thus, the regulation of SETD2 levels through intrinsically disordered region-facilitated proteolysis is important to maintain the fidelity of transcription and splicing related processes.

show abstract

Functional Studies on Primary Tubular Epithelial Cells Indicate a Tumor Suppressor Role of SETD2 in Clear Cell Renal Cell Carcinoma

Cited by 24 publications

References 31 publications

SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation

SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation

Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition

The disordered regions of SETD2 govern H3K36me3 deposition by regulating its proteasome-mediated decay

Contact Info

Product

Resources

About