Abstract
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.
Highlights
Multicellular organisms use genetically determined cell death mechanisms – most prominently apoptosis – to ensure the timely and innocuous removal of superfluous, damaged, or potentially harmful cells
Our observations indicate that rpoa-2(op259) mutants have no gross defect in cell cycle arrest response or double strand breaks (DSB)-repair
Consistent with the hypothesis that rpoa2(op259) mutants are resistant to CEP-1-dependent apoptosis, we found that rpoa-2(op259) could suppress the strongly increased baseline levels of germ cell apoptosis in the dsDNA break repair mutant rad-51(lg8701) (Fig. S13C) as well as the hypersensitivity to irradiation-induced apoptosis in in the Abl kinase mutant abl-1(ok171) (Fig. S13B), both of which involve CEP-1 [70]
Summary
Multicellular organisms use genetically determined cell death mechanisms – most prominently apoptosis – to ensure the timely and innocuous removal of superfluous, damaged, or potentially harmful cells. Apoptosis is tightly regulated and an integral part of the delicate balance between cell proliferation and cell loss, which is essential for the formation and maintenance of tissues and organs. Depending on the cell type, cell cycle stage, metabolic state and probably tissue context, excessive DNA damage can be a strong stimulus for cells to undergo apoptosis. Detailed knowledge of the DNA damage response network and its failures is required for our understanding of tumor formation and progression; and for effective and safe tumor treatment, as many of the current treatments produce DNA damage to induce replicative arrest or death of rapidly proliferating tumor cells
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