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

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.

Fahey CC ，Davis IJ 《Cold Spring Harbor Perspectives in Medicine》

Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation.

The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers. Whereas one of these mutations (R2510H), located in the Set2 Rpb1 interaction domain, did not result in an observable defect in SETD2 enzymatic function, a second mutation in the catalytic domain of this enzyme (R1625C) resulted in a complete loss of histone H3 Lys-36 trimethylation (H3K36me3). This mutant showed unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail. Surprisingly, mutation of the conserved residue in Set2 (R195C) similarly resulted in a complete loss of H3K36me3 but did not affect dimethylated histone H3 Lys-36 (H3K36me2) or functions associated with H3K36me2 in yeast. Collectively, these data imply a critical role for Arg-1625 in maintaining the protein interaction with H3 and specific H3K36me3 function of this enzyme, which is conserved from yeast to humans. They also may provide a refined biochemical explanation for how H3K36me3 loss leads to genomic instability and cancer.

Hacker KE ，Fahey CC ，Shinsky SA ，Chiang YJ ，DiFiore JV ，Jha DK ，Vo AH ，Shavit JA ，Davis IJ ，Strahl BD ，Rathmell WK ... -  《-》

Shaping the cellular landscape with Set2/SETD2 methylation.

McDaniel SL ，Strahl BD 《-》

SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle.

Gautam D ，Johnson BA ，Mac M ，Moody CA ... -  《-》

SETD2 as a regulator of N6-methyladenosine RNA methylation and modifiers in cancer.

Kumari S ，Muthusamy S 《-》