Academic journal article Genetics

ALG-2/AGO-Dependent Mir-35 Family Regulates DNA Damage-Induced Apoptosis through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis Elegans

Academic journal article Genetics

ALG-2/AGO-Dependent Mir-35 Family Regulates DNA Damage-Induced Apoptosis through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis Elegans

Article excerpt

APOPTOSIS describes the process of programmed cell death required to eliminate aberrant and damaged cells during development, or in response to stress. Upon DNA damage, proper regulation of apoptosis induction is essential to protect the organism from tissue deterioration and tumor formation (Thompson 1995). The Caenorhabditis elegans germline has proven to be a valuable model system to study the processes that regulate apoptosis in response to genotoxicity inflicted by ionizing radiation (IR) (Gumienny et al. 1999; Gartner et al. 2000). According to the canonical model, DNA-damage checkpoint signaling triggers phosphoactivation of the C. elegans p53-like protein CEP-1, which in turn selectively promotes apoptosis in late-pachytene germ cells by mediating the transcriptional upregulation of the two BH3-only genes egl-1 and ced-13 (Gartner et al. 2000; Derry et al. 2001; Schumacher et al. 2001, 2005b; Hofmann et al. 2002). Both CEP-1 targets antagonize the antiapoptotic Bcl-2 protein CED-9, which resides on the mitochondrial surface and normally restrains the proapoptotic Apaf-1 adaptor protein CED-4 from apoptosome formation and subsequent activation of the caspase homolog CED-3 (Yuan and Horvitz 1990; Wu et al. 1997; Xue and Horvitz 1997; Conradt and Horvitz 1998; del Peso et al. 1998; Yang et al. 1998; Gumienny et al. 1999; Hofmann et al. 2002; Conradt and Xue 2005; Schumacher etal. 2005b). However, this canonical model has been challenged by cytological studies that have demonstrated that instead of being sequestered by CED-9 at mitochondria of living cells, the CED-4 protein localizes predominantly to the perinuclear space (Pourkarimi et al. 2012). Therefore, it remains mechanistically unclear how cells initiate apoptosis downstream of CEP-1 and its transcriptional targets. Numerous factors and pathways have been identified to impinge on the regulation of DNA damage-induced apoptosis, in parallel or downstream, of CEP-1 and EGL-1/CED13, indicating that upregulation of BH3-only genes alone might be insufficient to fully commit a cell to apoptosis upon genotoxic stress (Reddien et al. 2007; Schertel and Conradt 2007; Greiss et al. 2008).

MAPK signaling is a major driver of gene expression in eukaryotic cells and mediates fundamental cellular processes including cell growth, differentiation, and death (LAllemain 1994; Tibbles and Woodgett 1999). In C. elegans, the extracellular signal-regulated kinase (ERK1/2) MAPK ortholog MPK-1 represents the terminal regulator of a highly conserved signaling cascade that involves the Ras GTPase LET60, the Raf MAPK kinase kinase LIN-45, and the MAPK kinase Mek ortholog MEK-2 that ultimately phosphorylates MPK-1 (Lackner et al. 1994; Wu and Han 1994; Sundaram 2013). In the C. elegans germline, MPK-1 drives meiotic germ cell progression, physiological germ cell death, and oocyte maturation (Church et al. 1995; Gumienny et al. 1999; Lee et al. 2007). MPK-1 furthermore becomes phosphorylated in latepachytene and diplotene germ cells in response to DNA damage where it is required to ensure proper apoptosis induction, presumably by mediating CEP-1/p53 expression and activity (Rutkowski etal. 2011). However, the molecular mechanisms that trigger MPK-1 phosphorylation in response to DNA damage are not well understood (Rutkowski et al. 2011; Ermolaeva et al. 2013). In addition, the essential function of MPK-1 in driving germ cells through meiotic prophase I complicates the study of its exact role and relevance during the killing process of late-pachytene germ cells (Lee et al. 2007).

MicroRNAs (miRNAs) are single-stranded, endogenously transcribed RNA molecules, 19-25 nt in length, that associate with specialized argonaute (AGO) proteins as well as other associated factors to post-transcriptionally silence gene expression by complementarily binding to the 3'-UTR of target mRNAs (Bartel 2004; Friedman et al. 2009; Ha and Kim 2014). In mammalian systems, miRNAs have been identified to modulate the expression of various DNA damage-response and apoptosis factors, and thus have been linked to cell transformation and tumor progression. …

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