The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms

The SIR genes are determinants of life span in yeast mother cells. Here we show that life spall regulation by the Sir proteins is independent of their role in nonhomologous end joining. The short life span of a sir3 or sir4 m utant is due to the simultaneous expression of a and alpha mating-type info rmation, which indirectly causes an increase in rDNA recombination and like ly increases the production of extrachromosomal rDNA circles. The short lif e span of a sir2 mutant also reveals a direct failure to repress recombinat ion generated by the Fob1p-mediated replication block in the rDNA. Sir2p is a limiting component in promoting yeast longevity, and increasing the gene dosage extends the life span in wild-type cells. A possible role of the co nserved SIR2 in mammalian aging is discussed.