RT Journal Article SR Electronic T1 The benzene hematotoxic and reactive metabolite 1,4-benzoquinone impairs the activity of the histone methyltransferase SETD2 and causes aberrant H3K36 trimethylation (H3K36me3) JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP MOLPHARM-AR-2021-000303 DO 10.1124/molpharm.121.000303 A1 Jérémy Berthelet A1 Christina Michail A1 Linh-Chi Bui A1 Louise Le Coadou A1 Valentina Sirri A1 Li Wang A1 Nicolas Dulphy A1 Jean-Marie Dupret A1 Christine Chomienne A1 Fabien Guidez A1 Fernando Rodrigues-Lima YR 2021 UL http://molpharm.aspetjournals.org/content/early/2021/07/03/molpharm.121.000303.abstract AB Human SETD2 is the unique histone methyltransferase that generates H3K36me3, an epigenetic mark that plays a key role in normal hematopoiesis. Interestingly, recurrent-inactivating mutations of SETD2 and aberrant H3K36 trimethylation (H3K36me3) are increasingly reported to be involved in hematopoietic malignancies. Benzene (BZ) is an ubiquitous environmental pollutant and carcinogen that causes leukemia. The leukemogenic properties of BZ depend on its biotransformation in the bone marrow into oxidative metabolites in particular 1,4-benzoquinone (BQ). This hematotoxic metabolite can form DNA and protein adducts that result in the damage and the alteration of cellular processes. Recent studies suggest that BZ-depend leukemogenesis could depend on epigenetic perturbations notably aberrant histone methylation. We investigated whether H3K36 trimethylation by SETD2 could be impacted by BZ and its hematotoxic metabolites. Herein, we show that BQ, the major leukemogenic metabolite of BZ, inhibits irreversibly the human histone methyltransferase SETD2 resulting in decreased H3K36 trimethylation (H3K36me3). Our mechanistic studies further indicate that the BQ-dependent inactivation of SETD2 is due to covalent binding of BQ to reactive Zn-finger cysteines within the catalytic domain of the enzyme. The formation of these quinoprotein adducts results in loss of enzyme activity and protein cross-links/oligomers. Experiments conducted in hematopoietic cells confirm that exposure to BQ results in the formation of SETD2 cross-links/oligomers and concomitant loss of H3K36me3 in cells. Taken together, our data indicate that BQ, a major hematotoxic metabolite of BZ could contribute to BZ-dependent leukemogenesis by perturbing the functions of SETD2, an histone lysine methyltransferase of hematopoietic relevance. Significance Statement Benzoquinone is a major leukemogenic metabolite of benzene. Dysregulation of histone methyltransferase is involved in hematopoietic malignancies. We found that benzoquinone irreversibly impairs SETD2, a histone H3K36 methyltransferase that plays a key role in hematopoiesis. Benzoquinone forms covalent adducts on Zn-finger cysteines within the catalytic site leading to loss of activity, protein cross-links/oligomers and concomitant decrease of H3K36me3 histone mark. Our data provide evidence that a leukemogenic metabolite of benzene can impair a key epigenetic enzyme.