title: Ribosome synthesis and MAPK activity modulate ionizing radiation-induced germ cell apoptosis in Caenorhabditis elegans.
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.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland ; MLS Graduate School and MD/PhD program, Zurich, Switzerland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Eberhard
authors.forename: Lilli
authors.initials: L
authors.lastname: Stergiou
authors.forename: E Randal
authors.initials: ER
authors.lastname: Hofmann
authors.forename: Jen
authors.initials: J
authors.lastname: Hofmann
authors.forename: Simon
authors.initials: S
authors.lastname: Haenni
authors.forename: Youjin
authors.initials: Y
authors.lastname: Teo
authors.forename: André
authors.initials: A
authors.lastname: Furger
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hengartner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D005854:Germ Cells / Q000528:radiation effects; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D012318:RNA Polymerase I / Q000235:genetics; D012335:RNA, Ribosomal / Q000096:biosynthesis* / Q000528:radiation effects; D011839:Radiation, Ionizing; D012270:Ribosomes / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53; D020929:Mitogen-Activated Protein Kinase Kinases; D012318:RNA Polymerase I