Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 May 1;7(5):a026468.
doi: 10.1101/cshperspect.a026468.

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

Catherine C Fahey  1 , Ian J Davis  1   2
Affiliations
Review

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

Catherine C Fahey et al. Cold Spring Harb Perspect Med. .

Abstract

The H3 lysine 36 histone methyltransferase SETD2 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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
H3K36 methyltransferases. Methyltransferases shown to mono-, di-, and trimethylate H3K36. Those shown in bold have been shown in cell-based assays and/or in vivo. (Figure adapted from data in Wagner and Carpenter 2012.)
Figure 2.
Figure 2.
Schematic representation of SETD2 and cancer-associated mutations. SETD2 domains: AWS (associated with SET), SET (Su(var)3-9, enhancer-of-zeste, trithorax), PS (post-SET), CC (coiled coil), LCR (low charge region), WW, SRI (Set2 Rpb1 Interacting). Mutation lists were obtained from CBioPortal on February 5, 2016, and separated into cancer types. Duplicates were removed. Mutations are plotted by color (cancer type) and shape (mutation type). ccRCC, Clear cell renal cell carcinoma; pRCC, papillary renal cell carcinoma.
Figure 3.
Figure 3.
Transcription and RNA processing. SETD2 associates with RNAPII to posttranslationally modify nucleosomes. H3K36me3 is directly bound by readers, which mediate RNA processing through downstream effectors.
Figure 4.
Figure 4.
DNA damage repair. Specific H3K36me3 readers direct either homologous recombination (top) or mismatch repair (bottom).
See this image and copyright information in PMC

References

    1. Al Sarakbi W, Sasi W, Jiang WG, Roberts T, Newbold RF, Mokbel K. 2009. The mRNA expression of SETD2 in human breast cancer: Correlation with clinico-pathological parameters. BMC Cancer 9: 290. - PMC - PubMed
    1. Awwad SW, Ayoub N. 2015. Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway. Biol Open 4: 498–504. - PMC - PubMed
    1. Aymard F, Bugler B, Schmidt CK, Guillou E, Caron P, Briois S, Iacovoni JS, Daburon V, Miller KM, Jackson SP, et al. 2014. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat Struct Mol Biol 21: 366–374. - PMC - PubMed
    1. Bannister AJ, Schneider R, Myers F a, Thorne AW, Crane-Robinson C, Kouzarides T. 2005. Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes. J Biol Chem 280: 17732–17736. - PubMed
    1. Baubec T, Colombo DF, Wirbelauer C, Schmidt J, Burger L, Krebs AR, Akalin A, Schübeler D. 2015. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520: 243–247. - PubMed