cku-70;daf-16;daf-2

Caenorhabditis KU

Locus: CELE_Y47D3A.4

Wormbase description: cku-70 encodes an ortholog of human XRCC6 (Ku70; OMIM:152690, antigen of systemic lupus erythematosus); CKU-70 is required for resistance to ionizing radiation (IR) in somatic tissues (such as motor neurons, vulva or uterus) and in endoreduplicating intestinal cells, but not in the germline; CKU-70 is also required for survival of dauer larvae subjected to IR, and for resistance of developing embryos to methyl methane sulfonate; CKU-70, unlike CKU-80, inhibits DAF-16-dependent thermotolerance, and slightly shortens normal lifespan; CKU-70 binds CKU-80 in yeast two-hybrid assays, and requires HIM-10 for fully effective DNA repair in somatic cells; by orthology, CKU-70 is expected to function (as a heterodimer with CKU-80) in nonhomologous end-joining of double-stranded breaks in DNA; mutant cku-70 late-stage embryos or dauer larvae are hypersensitive to radiation-induced DNA damage in somatic cells; after irradiation, cku-70 mutants tend to display various postembryonic phenotypes (such as slow growth, uncoordinated locomotion, impaired egg-laying, or vulval defects) that are enhanced by him-10 mutations, and that are thought to reflect missegregation of fragmented chromosomes; cku-70(RNAi) animals show a minor extension of lifespan in an rrf-3(pk1426) mutant background, independently of the presence or absence of either functional DAF-2 or germline cells, but a reduction of lifespan with a loss of DAF-16 activity.

Forkhead box protein O;hypothetical protein

Locus: CELE_R13H8.1

Wormbase description: daf-16 encodes the sole C. elegans forkhead box O (FOXO) homologue; DAF-16 functions as a transcription factor that acts in the insulin/IGF-1-mediated signaling (IIS) pathway that regulates dauer formation, longevity, fat metabolism, stress response, and innate immunity; DAF-16 regulates these various processes through isoform-specific expression, isoform-specific regulation by different AKT kinases, and differential regulation of target genes; DAF-16 can interact with the CBP-1 transcription cofactor in vitro, and interacts genetically with other genes in the insulin signaling and with daf-12, which encodes a nuclear hormone receptor; DAF-16 is activated in response to DNA damage during development and co-regulated by EGL-27, alleviates DNA-damage-induced developmental arrest by inducing DAF-16-associated element (DAE)-regulated genes; DAF-16 is broadly expressed but displays isoform-specific tissue enrichment; DAF-16 localizes to both the cytoplasm and the nucleus, with the ratio between the two an important regulator of function.

Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein

Locus: CELE_Y55D5A.5

Wormbase description: daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle.