ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage.
Cell Death Dis
; 8(7): e2947, 2017 07 20.
Article
de En
| MEDLINE
| ID: mdl-28726787
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Dégénérescences spinocérébelleuses
/
Caractères sexuels
/
Cellules photoréceptrices de vertébré
/
Agents alcoylants
/
AlkB enzymes
Limites:
Animals
/
Female
/
Humans
/
Male
Langue:
En
Journal:
Cell Death Dis
Année:
2017
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique