期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 38, 页码 9598-9603出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1806355115
关键词
histone mutation; SETD2; histone methylation; mismatch repair
资金
- National Institutes of Health [GM112702, CA192003]
- National Natural Science Foundation of China [31370766, 31570814, 31725014, 81630077]
- National Natural Science Foundation of China-Israel Science Foundation Joint Research Program [31461143005]
- Cancer Prevention and Research Institute of Texas [RR160101]
- Tsinghua-Peking Joint Center for Life Sciences
- Reece A. Overcash Jr. Center for Research on Colon Cancer at University of Texas Southwestern Medical Center
- NATIONAL CANCER INSTITUTE [R21CA192003] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM112702] Funding Source: NIH RePORTER
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 MutS alpha, 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.
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