Abstract
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.
Highlights
Certain environmental or pathological conditions can trigger a regulated form of necrotic cell death characterized by cytoplasmic swelling, vacuolization and rupture of the plasma membrane with subsequent stimulation of the inflammatory response
Chemotherapeutic alkylating agents can trigger a regulated form of necrosis that is dependent upon hyperactivation of polyADP-ribose polymerase 1 (PARP1; known as ADPribosyltransferase and diphtheria toxin-like 1, ARTD1).[10,11,12,13,14]
We have previously shown that human AlkB homolog 7 (ALKBH7) is a mitochondrial protein required for PARP1/ ARTD1-dependent regulated necrosis stimulated by alkylating and oxidizing agents.[28]
Summary
Certain environmental or pathological conditions can trigger a regulated form of necrotic cell death characterized by cytoplasmic swelling, vacuolization and rupture of the plasma membrane with subsequent stimulation of the inflammatory response (reviewed in references 1–5). Chemotherapeutic alkylating agents can trigger a regulated form of necrosis that is dependent upon hyperactivation of polyADP-ribose polymerase 1 (PARP1; known as ADPribosyltransferase and diphtheria toxin-like 1, ARTD1).[10,11,12,13,14] PARP1/ARTD1-dependent cell death, known as parthanatos, has been shown to have a major role in cell death induced by physiological conditions such as ischemia reperfusion, Parkinson’s and uncontrolled diabetes (reviewed in Fatokun et al.[15] and Ying and Padanilam[16]). In addition to human and mouse cells, we demonstrate that ALKBH7 has a key role in mediating
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