Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis
Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis
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DOI：
10.1101/gad.215533.113
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发表时间：
2013-05-15
影响因子：
10.5
通讯作者：
Samson, Leona D.
中科院分区：
文献类型：
--
作者：
Fu, Dragony;Jordan, Jennifer J.;Samson, Leona D.
程序性坏死已成为细胞死亡的一个重要调节因子，以响应几种形式的细胞应激。在由细胞毒性烷化剂诱导的程序性坏死细胞死亡的一种形式中，聚ADP-核糖聚合酶（PARP）的超活化导致细胞NAD和ATP耗竭、线粒体功能障碍、活性氧物质形成和随后的细胞死亡。在这里，我们表明，由人类AlkB同系物7（ALKBH 7）基因编码的蛋白质在DNA损伤剂诱导的程序性坏死中起着关键作用，通过触发线粒体膜电位的崩溃和线粒体功能的大规模丧失，导致能量耗尽和细胞死亡。ALKBH 7的消耗抑制由许多烷化剂和氧化剂诱导的坏死性细胞死亡，而对凋亡性细胞死亡没有影响。与野生型细胞一样，ALKBH 7耗尽的细胞在严重DNA损伤后经历PARP超活化和NAD耗尽，但与野生型细胞不同，其表现出细胞内NAD和ATP水平的快速恢复。与细胞生物能量学的恢复一致，ALKBH 7耗尽的细胞保持其线粒体膜电位、质膜完整性和活力。我们的研究结果揭示了哺乳动物AlkB同系物在程序性坏死中的新作用，为耐凋亡细胞死亡的癌细胞的治疗干预提供了新的靶点。
Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering the collapse of mitochondrial membrane potential and large-scale loss of mitochondrial function that lead to energy depletion and cellular demise. Depletion of ALKBH7 suppresses necrotic cell death induced by numerous alkylating and oxidizing agents while having no effect on apoptotic cell death. Like wild-type cells, ALKBH7-depleted cells undergo PARP hyperactivation and NAD depletion after severe DNA damage but, unlike wild-type cells, exhibit rapid recovery of intracellular NAD and ATP levels. Consistent with the recovery of cellular bioenergetics, ALKBH7-depleted cells maintain their mitochondrial membrane potential, plasma membrane integrity, and viability. Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death.