Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3–MutSα interaction

Abstract

Somatic mutations on glycine 34 of histone H3 (H3G34) cause pediatric cancers, but the underlying oncogenic mechanism remains unknown. We demonstrate that substituting H3G34 with arginine, valine, or aspartate (H3G34R/V/D), which converts the non-side chain glycine to a large side chain-containing residue, blocks H3 lysine 36 (H3K36) dimethylation and trimethylation by histone methyltransferases, including SETD2, an H3K36-specific trimethyltransferase. Our structural analysis reveals that the H3 "G33-G34" motif is recognized by a narrow substrate channel, and that H3G34/R/V/D mutations impair the catalytic activity of SETD2 due to steric clashes that impede optimal SETD2-H3K36 interaction. H3G34R/V/D mutations also block H3K36me3 from interacting with mismatch repair (MMR) protein MutSα, preventing the recruitment of the MMR machinery to chromatin. Cells harboring H3G34R/V/D mutations display a mutator phenotype similar to that observed in MMR-defective cells. Therefore, H3G34R/V/D mutations promote genome instability and tumorigenesis by inhibiting MMR activity.

Mutation bias shapes gene evolution in Arabidopsis thaliana

“…The observed negative correlation between GC content and mutation rate was consistent with other observations of lower mutation rate in GC rich regions 23,[39][40][41][42] and mechanistically with both GC biased gene conversion 43 and lower rates of cytosine deamination in GC rich regions 10,[44][45][46][47] . Furthermore, the histone modifications H3K4me1 and H3K27ac are known to be associated with lower mutation rates, particularly in active genes 21,[48][49][50] , and several studies have revealed explicit connections between H3K36me3 and DNA mismatch repair 13,16,17 . These chromatin marks were enriched in gene bodies (Fig.…”

“…And while reports of non-random relationships between mutation rates and fitness consequences have been previously made, these have been questioned because they have largely relied on substitution rates in natural populations rather than direct measures of de novo mutations 3,9-12 .More recently though, discoveries in genome biology have inspired a reevaluation of classical theories of mutation rate evolution. It is now recognized that mutation rates across genomes are influenced by DNA sequence composition, epigenomic features, and bias in the targets of DNA repair mechanisms 5,6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . It is also known that broad classes of genes (e.g., housekeeping genes) exist in distinct cytogenetic (DNA sequence + epigenomic) states.…”

H3K36me3, message from chromatin to DNA damage repair

“…H3K36me3 may negatively impede DSBs by restricting chromatin accessibility through nucleosome positioning or, more directly, by favoring the repair of DSBs [73,74]. Disruption of H3K36me3 coupled DSBs repair inhibits the immunoglobulin V(D)J rearrangement in B cells [75] and promotes tumorigenesis of aggressive cancers, such as clear cell renal cell carcinoma (ccRCC) [76], acute myeloid leukemia (AML) [77], and diffuse intrinsic pontine glioma (DIPG) [78].…”

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

“…Intriguingly, mutations in SETD2, an H3K36 methylase have been found in pHGG and they are mutually exclusive with H3G34R/V mutations, suggesting they may act through a common mechanism ; however, the low overall frequency of H3G34R/V and SETD2 mutations could also account for this observation. H3G34R/V mutations have been shown to block di‐ and trimethylation of H3K36 because of steric hindrance and mutation of the H3G34 residue on the same peptide as H3K36M relieves the dominant effect of H3K36M on H3K36me3 by decreasing the stable interaction of the H3 tail with SETD2 . Surprisingly, H3G34R has been reported to result in a local increase of H3K36me3 at specific loci, including MYCN .…”

“…Fission yeast engineered to express only H3G34R exhibit genome instability and is defective for DNA damage repair by homologous recombination and mammalian cells overexpressing H3G34R/V display a hypermutator phenotype . However, unlike H3K27M, H3G34R/V gave no growth advantage to NPCs in culture , nor was introduction of H3G34R and p53 loss into NPCs in the embryonic forebrain able to produce tumours, unlike H3K27M in the same setting .…”