title: RAD-6: pyrimidine synthesis and radiation sensitivity in Caenorhabditis elegans.
abstract: The Caenorhabditis elegans rad-6 (radiation-sensitive-6) mutant was isolated over 25 years ago in a genetic screen that identified mutants with enhanced sensitivity to DNA damaging agents. In the present paper we describe the molecular identification of the rad-6 gene and reveal that it encodes the bifunctional UMP synthase protein, which carries catalytic activities for OPRTase (orotate phosphoribosyltransferase) and ODCase (orotate monophosphate decarboxylase), key enzymes in the de novo pathway of pyrimidine synthesis. Mutations in genes encoding de novo pathway enzymes cause varying degrees of lethality and pleiotropic phenotypes in many organisms, including humans. We have examined how the absence of rad-6 activity leads to both UV-C hypersensitivity and a decline in both metabolic rate and lifespan. We discuss how rad-6 mutants adapt to the loss of the de novo pathway through a dependency on pyrimidine salvage. We establish further that rad-6(mn160) mutants lack ODCase activity because they are resistant to the cytotoxic effects of 5-FOA (5-fluoroorotic acid). Our results have also led to the identification of a metabolic sensor affecting survival and metabolism, which is dependent on the maternal rad-6 genotype.
authors.affiliation: *University of Bristol, School of Biochemistry, Bristol BS8 1TD, U.K.
authors.forename: Alyce
authors.initials: A
authors.lastname: Merry
authors.affiliation: *University of Bristol, School of Biochemistry, Bristol BS8 1TD, U.K.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Qiao
authors.affiliation: *University of Bristol, School of Biochemistry, Bristol BS8 1TD, U.K.
authors.forename: Martin
authors.initials: M
authors.lastname: Hasler
authors.affiliation: *University of Bristol, School of Biochemistry, Bristol BS8 1TD, U.K.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Kuwabara
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000528:radiation effects*; D008136:Longevity / Q000235:genetics / Q000528:radiation effects; D009097:Multienzyme Complexes / Q000235:genetics; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000235:genetics; D011743:Pyrimidines / Q000096:biosynthesis*; D011836:Radiation Tolerance / Q000235:genetics*; D011838:Radiation-Sensitizing Agents
chemical_list: D029742:Caenorhabditis elegans Proteins; D009097:Multienzyme Complexes; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; C027157:uridine 5'-monophosphate synthase; D009962:Orotate Phosphoribosyltransferase; D009964:Orotidine-5'-Phosphate Decarboxylase; C030986:pyrimidine