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

作者：Jordan Jennifer J; Chhim Sophea; Margulies Carrie M; Allocca Mariacarmela; Bronson Roderick T; Klungland Arne; Samson Leona D^*; Fu Dragony^*

来源：Cell Death & Disease, 2017, 8(7): e2947.

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.

• 出版日期2017-7
• 单位MIT