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The H3K36 histone methyltransferase SETD2 as a target of leukemogenic chemicals: molecular and cellular studies.
Author(s) -
BERTHELET Jérémy,
DUVAL Romain,
BUI LinhChi,
MATHIEU Cécile,
PETIT Emile,
DUPRET JeanMarie,
GUIDEZ Fabien,
CHOMIENNE Christine,
RODRIGUESLIMA Fernando
Publication year - 2018
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.2018.32.1_supplement.524.10
Subject(s) - carcinogen , histone , histone methyltransferase , methyltransferase , epigenetics , chemistry , dna damage , demethylase , biology , cancer research , biochemistry , microbiology and biotechnology , gene , methylation , dna
SETD2 is a key histone modifying enzyme that is responsible for the trimethylation of lysine 36 of histone H3 (H3K36me3) in mammals. During transcriptional elongation in normal cells, H3K36me3 marks the zone on exons for accurate gene transcription and plays an important role in the regulation of alternative splicing. In addition, SETD2‐mediated H3K36me3 is required for DNA repair and recruitment of other epigenetic enzymes. Several studies have shown that loss of function mutations in SETD2 are involved in cancer development. In particular, SETD2 inactivating mutations have been shown to be critical drivers in leukemia development. Benzene (BZ) is a chemical of great industrial interest. BZ is also known to be a major hazardous air pollutant originating from anthropogenic (road transport, tobacco smoke, etc) and natural sources (forest fires). BZ is classified as a class I human carcinogen. Environmental and occupational exposure to BZ lead to bone marrow malignancies such as leukemia. The leukemogenic effects of BZ relies on its metabolization in lungs and bone marrow cells into reactive metabolites, in particular benzoquinone (BQ). However, most of the key molecular and cellular mechanisms underlying its hematotoxicity are not fully understood. Here we provide evidence that SETD2 is a target of BQ, the prime hematotoxic metabolite of BZ. Using a specific HPLC based SETD2 assay, we found that the methyltransferase activity of SETD2 is readily inhibited by BQ in vitro and in cellulo in an irreversible manner ( k inact =300 M −1 .s −1 ). This inhibition is due to the covalent modification (arylation) of cysteine residues present in Zn 2+ finger motifs (AWS and post‐SET domains) by BQ with concomitant release of Zn 2+ . Accordingly, exposure of cells (K562 or HEK293T) to BQ leads to global loss of H3K36me3. The H3K36 histone methyltransferase SETD2 is increasingly recognized as a tumor suppressor gene, which can facilitate the initiation and maintenance of leukemia. Our data suggest that BQ, the major hematoxic metabolite of benzene, can impair the functions of SETD2 which may contribute to benzene‐dependent leukemogenesis. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .