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

Jun Fang, Yaping Huang, Guogen Mao, Shuang Yang, Gadi Rennert, Liya Gu, Haitao Li, Guo Min Li

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9598-9603
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number38
DOIs
StatePublished - Sep 18 2018

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DNA Mismatch Repair
Methylation
Mutation
Neoplasms
Glycine
Genomic Instability
Valine
Aspartic Acid
Histones
Lysine
Chromatin
Arginine
Carcinogenesis
Pediatrics
Phenotype
Proteins

Keywords

  • Histone methylation
  • Histone mutation
  • Mismatch repair
  • SETD2

ASJC Scopus subject areas

  • General

Cite this

Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3-MutSα interaction. / Fang, Jun; Huang, Yaping; Mao, Guogen; Yang, Shuang; Rennert, Gadi; Gu, Liya; Li, Haitao; Li, Guo Min.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 38, 18.09.2018, p. 9598-9603.

Research output: Contribution to journalArticle

Fang, Jun ; Huang, Yaping ; Mao, Guogen ; Yang, Shuang ; Rennert, Gadi ; Gu, Liya ; Li, Haitao ; Li, Guo Min. / Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3-MutSα interaction. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 38. pp. 9598-9603.
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