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Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3-MutSĪ± interaction.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 9/18/2018, Vol. 115 Issue 38, p9598-9603. 6p. - Publication Year :
- 2018
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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 MutSĪ±, 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *GENETIC mutation
*GLYCINE
*METHYLATION
*HUMAN genome
*NUCLEOPROTEINS
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 115
- Issue :
- 38
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 131916850
- Full Text :
- https://doi.org/10.1073/pnas.1806355115