MicroRNAs (miRNAs) associate with argonaute (AGO) proteins to post-transcriptionally modulate the expression of genes involved in various cellular processes. Herein, we show that loss of the Caenorhabditis elegans AGO gene alg-2 results in rapid and significantly increased germ cell apoptosis in response to DNA damage inflicted by ionizing radiation (IR). We demonstrate that the abnormal apoptosis phenotype in alg-2 mutant animals can be explained by reduced expression of mir-35 miRNA family members. We show that the increased apoptosis levels in IR-treated alg-2 or mir-35 family mutants depend on a transient hyperactivation of the C. elegans ERK1/2 MAPK ortholog MPK-1 in dying germ cells. Unexpectedly, MPK-1 phosphorylation occurs downstream of caspase activation and depends at least in part on a functional cell corpse-engulfment machinery. Therefore, we propose a refined mechanism, in which an initial proapoptotic stimulus by the core apoptotic machinery initiates the engulfment process, which in turn activates MAPK signaling to facilitate the demise of genomically compromised germ cells.

中文翻译：

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ALG-2/AGO 依赖性 mir-35 家族通过秀丽隐杆线虫核心凋亡机制下游的 MPK-1/ERK MAPK 信号下游调节 DNA 损伤诱导的细胞凋亡。


MicroRNA (miRNA) 与 argonaute (AGO) 蛋白结合，在转录后调节参与各种细胞过程的基因的表达。在此，我们发现，秀丽隐杆线虫 AGO 基因 alg-2 的缺失会导致生殖细胞凋亡快速且显着增加，以响应电离辐射 (IR) 造成的 DNA 损伤。我们证明 alg-2 突变动物中的异常凋亡表型可以通过 mir-35 miRNA 家族成员的表达减少来解释。我们表明，IR处理的alg-2或mir-35家族突变体中细胞凋亡水平的增加取决于垂死生殖细胞中线虫ERK1/2 MAPK直系同源物MPK-1的短暂过度激活。出乎意料的是，MPK-1 磷酸化发生在 caspase 激活的下游，并且至少部分依赖于功能性细胞尸体吞噬机制。因此，我们提出了一种改进的机制，其中核心凋亡机制的初始促凋亡刺激启动吞噬过程，进而激活 MAPK 信号传导以促进基因组受损的生殖细胞的死亡。