RRC ID 51419
Author González-Huici V, Wang B, Gartner A.
Title A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans.
Journal Genetics
Abstract Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hyper-sensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signaling pathways. Hyper-sensitivity to IR also occurs when other genes mediating NMD are mutated. The hyper-sensitivity to bleomycin, a drug known to induce DSBs, further supports that NMD pathway mutants are defective in DSB repair. Hyper-sensitivity was not observed upon treatment with alkylating agents or UV irradiation. We show that SMG-1 mainly acts in mitotically dividing germ cells, and during late embryonic and larval development. Based on epistasis experiments, SMG-1 does not appear to act in any of the three major pathways known to mend DNA DSBs, namely homologous recombination (HR), nonhomologous end-joining (NHEJ), and microhomology-mediated end-joining (MMEJ). We speculate that SMG-1 kinase activity could be activated following DNA damage to phosphorylate specific DNA repair proteins and/or that NMD inactivation may lead to aberrant mRNAs leading to synthesis of malfunctioning DNA repair proteins.
Volume 206(4)
Pages 1853-1864
Published 2017-8-1
DOI 10.1534/genetics.117.203414
PII genetics.117.203414
PMID 28634159
PMC PMC5560793
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / radiation effects Caenorhabditis elegans Proteins / genetics DNA Breaks, Double-Stranded DNA Damage DNA Repair Epistasis, Genetic Genomic Instability* Homologous Recombination Mitosis Nonsense Mediated mRNA Decay* Protein-Serine-Threonine Kinases / genetics Radiation, Ionizing
IF 4.015
Times Cited 3
Resource
C.elegans tm1145 tm2026 tm2842 tm2940