Long-lived mutants in the nematode Caenorhabditis elegans have been studied to determine if the mutations responsible for extended life were allelic. Three of four mutant strains studied (MK31, MK542, MK546) contain recessive mutations that significantly lengthen life; MK542 and MK546 consistently fail to complement the long life phenotype of age-1 and are therefore allelic. MK31, although longer lived than wild type, is equivocal, in some cases failing to complement age-1 but not in others. All three long-lived strains have reduced hermaphrodite self-fertility and also fail to complement for this presumed pleiotropic effect of the age-1 mutation. Each of these three strains also contains an independent mutation at unc-31 IV. Since the mutants were isolated in the same mutant hunt (Klass, 1983) using protocols that did not guarantee independence, the mutations cannot be assumed to be independently isolated.

http://sageke.sciencemag.org/cgi/reprint/2002/38/cp23.pdf

Three Mutants That Extend Both Mean and Maximum Life Span of the Nematode, Caenorhabditis elegans, Define the age-1 Gene

The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance. Here, we show that Sir3p is released from telomeres in response to DNA double-strand breaks (DSBs), binds to DSBs, and mediates their repair, independent of cell mating type. Sir3p relocalization is S phase specific and, importantly, requires the DNA damage checkpoint genes MEC1 and RAD9. MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs. This novel mode by which preformed DNA repair machinery is mobilized by DNA damage sensors may have implications for human diseases resulting from defective DSB repair.

MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks

Sirtuins are NAD-dependent protein deacetylases found in organisms ranging from bacteria to humans that share sequence homology with the yeast transcriptional regulator Sir2. In eukaryotes, sirtuins regulate The first two authors contributed equally to this review. transcriptional repression, recombination, cell cycle division, microtubule organization, and cellular responses to DNA-damaging agents. Sir2 proteins have also been implicated in regulating the molecular mechanisms of aging. Eukaryotic sirtuins contain a core catalytic domain and variable amino- and carboxyl-terminal extensions that regulate their subcellular localizations and catalytic activity. This review focuses on the diverse sub-cellular distribution, substrate specificity, and cellular functions of sirtuins with particular emphasis on the biology of mammalian sirtuins.

The Class III Protein Deacetylases

Ribaviren für den Gebrauch, um Krebs zu behandeln

La presente invention concerne des procedes d'identification d'agents qui modulent un niveau ou une activite d'un polypeptide de tubuline desacetylase. La presente invention traite egalement d'agents identifies par ces procedes. L'invention concerne aussi des procedes de modulation de l'activite de la tubuline desacetylase dans une cellule. L'invention a aussi pour objet des procedes de modulation de la proliferation cellulaire par la modulation de l'activite de la tubuline desacetylase.

Brian J. North

Papers

The Class III Protein Deacetylases

Ribaviren für den Gebrauch, um Krebs zu behandeln

Procedes de modulation de l'activite de la tubuline desacetylase

Ribaviren pour utilisation pour traiter le cancer