ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage.
ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage.
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DOI：
10.1038/cddis.2017.343
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发表时间：
2017-07-20
影响因子：
9
通讯作者：
Fu D
中科院分区：
文献类型：
--
作者：
Jordan JJ;Chhim S;Margulies CM;Allocca M;Bronson RT;Klungland A;Samson LD;Fu D
调节性坏死已成为响应不同形式的生理和药理学应激的主要细胞死亡机制。AlkB同源物7（ALKBH 7）蛋白是响应于化疗烷化剂的调节性细胞坏死所需的，但其在整个生物体中的作用尚不清楚。在这里，我们表明ALKBH 7通过组织和性别特异性机制调节烷基化诱导的细胞死亡。在整个动物水平上，我们发现ALKBH 7缺乏在雄性而不是雌性小鼠中赋予对MMS诱导的毒性的抗性增加。此外，ALKBH 7缺陷型小鼠在视网膜感光细胞和小脑颗粒细胞中表现出对烷基化介导的细胞毒性的保护作用，这两种细胞类型通过启动碱基切除修复途径和PARP 1/ARTD 1酶的超活化而发生坏死性死亡。值得注意的是，对烷基化诱导的小脑变性的保护是特异性的ALKBH 7缺陷的雄性小鼠，而不是雌性小鼠。我们的研究结果揭示了ALKBH 7在介导对烷基化损伤的性二态组织反应中的体内作用，这可能影响基于烷基化剂的化疗的个体反应。
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.
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