ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage

• Published in: Cell death & disease Vol. 8; no. 7; p. e2947
• Main Authors: Jordan, Jennifer J, Chhim, Sophea, Margulies, Carrie M, Allocca, Mariacarmela, Bronson, Roderick T, Klungland, Arne, Samson, Leona D, Fu, Dragony
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.07.2017
• Subjects: AlkB Enzymes - genetics; AlkB Enzymes - metabolism; Alkylating Agents - adverse effects; Alkylating Agents - pharmacology; Animals; Female; HEK293 Cells; Humans; Male; Mice; Mice, Knockout; Necrosis; Original; Photoreceptor Cells, Vertebrate - metabolism; Photoreceptor Cells, Vertebrate - pathology; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Sex Characteristics; Spinocerebellar Degenerations - chemically induced; Spinocerebellar Degenerations - genetics; Spinocerebellar Degenerations - metabolism; Spinocerebellar Degenerations - pathology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.343

Regulated necrosis has emerged as a major cell death mechanism in response to different forms of physiological and pharmacological stress. The AlkB homolog 7 (ALKBH7) protein is required for regulated cellular necrosis in response to chemotherapeutic alkylating agents but its role within a whole organism is unknown. Here, we show that ALKBH7 modulates alkylation-induced cellular death through a tissue and sex-specific mechanism. At the whole-animal level, we find that ALKBH7 deficiency confers increased resistance to MMS-induced toxicity in male but not female mice. Moreover, ALKBH7-deficient mice exhibit protection against alkylation-mediated cytotoxicity in retinal photoreceptor and cerebellar granule cells, two cell types that undergo necrotic death through the initiation of the base excision repair pathway and hyperactivation of the PARP1/ARTD1 enzyme. Notably, the protection against alkylation-induced cerebellar degeneration is specific to ALKBH7-deficient male but not female mice. Our results uncover an in vivo role for ALKBH7 in mediating a sexually dimorphic tissue response to alkylation damage that could influence individual responses to chemotherapies based upon alkylating agents.