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Impact of Histone Mutations on Mismatch Repair and Cancer
Author(s) -
Fang Jun
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.906.1
Subject(s) - carcinogenesis , dna mismatch repair , chromatin , mutagenesis , histone , methylation , mutation , methyltransferase , histone methyltransferase , histone h3 , chemistry , biology , cancer research , genetics , microbiology and biotechnology , dna repair , cancer , dna , gene
Mutations in histone 3 (H3), particularly H3K36M/I and H3G34V/R have been identified as novel drivers for several types of human cancer. Because H3K36me3 is essential for DNA mismatch repair (MMR) in vivo by recruiting mismatch recognition protein MutSa to replicating chromatin, cancers with H3K36M/I mutations are expected to have a defective MMR system, which leads to genome instability and cancer development. However, how H3G34V/R mutations confer tumorigenesis is unknown. Given that both Arg and Val contain a bigger side chain in comparison to Gly, we hypothesize that these big side chains at position 33 of H3 impairs H3K36 interactions with MutSa and/or SETD2, the major methyltransferase responsible for H3K36 trimethylation. We show here both in vitro and in vivo evidence that G34V/R mutations block H3K36 trimethylation and its interaction with MutSa. The crystal structures of the SETD2 catalytic domain bound to H3K36 peptide with SAH (S‐adenosylhomocysteine) reveal that the SETD2 catalytic domain adopts an open conformation, with the K36 peptide snuggly positioned in a newly formed substrate channel, which is essential for SETD2‐H3K36 interaction. It is obvious that substitution of G34 with V34 or R34 obstructs the catalytic domain and the SETD2‐H3K36 interaction. We therefore conclude that like H3K36M/I mutations, H3G34V/R mutations promote mutagenesis and tumorigenesis by blocking MMR in vivo 1 Impact of H3G34D/R/V on H3K36 methylation in vivo by Mas‐spec analysis. A. H3K36 methylation ratio in G1‐S boundary cell lines. B. H3K36 methylation ratio in unsynchronized cell lines. Unsynchronized cells have less H3K36me3 than G1‐S boundary cells.A H3K36 methylation ratio in G1‐S boundary cell linesH3.3‐WT H3.1‐WTnon 45.8% 93.8% 57.6% 82.9% 50.0% mono‐ 44.0% 1.7% 11.6% 16.3% 8.7% di‐ 9.4% 3.7% 16.2% 0.8% 14.2% tri‐ 0.8% 0.9% 14.6% 0.0% 27.1%B H3K36 methylation ratio in unsynchronized cell linesH3.3‐WT H3.1‐WTnon 56.2% 52.3% 37.3% 91.8% 30.8% mono‐ 27.9% 18.7% 18.9% 7.4% 18.0% di‐ 14.7% 26.2% 34.5% 0.8% 43.3% tri‐ 1.2% 2.8% 9.3% 0.0% 7.9%