RESUMEN
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.
Asunto(s)
Proteínas de Caenorhabditis elegans/biosíntesis , Proteínas de Caenorhabditis elegans/efectos de la radiación , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de la radiación , Pirimidinas/biosíntesis , Tolerancia a Radiación/genética , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Longevidad/genética , Longevidad/efectos de la radiación , Complejos Multienzimáticos/genética , Orotato Fosforribosiltransferasa/genética , Orotidina-5'-Fosfato Descarboxilasa/genética , Fármacos Sensibilizantes a RadiacionesRESUMEN
The nematode Caenorhabditis elegans is widely used as a model organism for studying many fundamental aspects of development and cell biology, including processes underlying human disease. The genome of C. elegans encodes over 19,000 protein-coding genes and hundreds of non-coding RNAs. The availability of whole genome sequence has facilitated the development of high throughput techniques for elucidating the function of individual genes and gene products. Furthermore, attempts can now be made to integrate these substantial functional genomics data collections and to understand at a global level how the flow of genomic information that is at the core of the central dogma leads to the development of a multicellular organism.
