Ribosome Synthesis and MAPK Activity Modulate Ionizing Radiation-Induced Germ Cell Apoptosis in Caenorhabditis elegans

Synthesis of ribosomal rna by rna polymerase i (rna pol i) is an elemental biological process and is key for cellular homeostasis. in a forward genetic screen in c. elegans designed to identify dna damage-response factors,we isolated a point mutation of rna pol i,rpoa-2(op259),that leads to altered rrna synthesis and a concomitant resistance to ionizing radiation (ir)-induced germ cell apoptosis. this weak apoptotic ir response could be phenocopied when interfering with other factors of ribosome synthesis. surprisingly,despite their resistance to dna damage,rpoa-2(op259) mutants present a normal cep-1/p53 response to ir and increased basal cep-1 activity under normal growth conditions. in parallel,rpoa-2(op259) leads to reduced ras/mapk pathway activity,which is required for germ cell progression and physiological germ cell death. ras/mapk gain-of-function conditions could rescue the ir response defect in rpoa-2(op259),pointing to a function for ras/mapk in modulating dna damage-induced apoptosis downstream of cep-1. our data demonstrate that a single point mutation in an rna pol i subunit can interfere with multiple key signalling pathways. ribosome synthesis and growth-factor signalling are perturbed in many cancer cells; such an interplay between basic cellular processes and signalling might be critical for how tumours evolve or respond to treatment. © 2013 eberhard et al.