Maintenance of chromatin silencing and genome stability by Sir2
Silencing of genomic DNA was first observed by repression of genes near certain translocation breakpoints in Drosophila (for review, see Wakimoto 1998). Studies in Drosophila and yeast have led to the identification of factors that act in trans to mediate silencing. Among these are the proteins encoded by the yeastSIR genes, which are responsible for silencing at repeated DNA sequences in yeast: mating type loci, telomeres, and the rDNA.SIR2, SIR3, and SIR4 are all required for silencing at mating type loci (Rine and Herskowitz 1987) and telomeres (Gottschling et al. 1990), and SIR2, but not SIR3 orSIR4, is required for silencing in the rDNA (Bryk et al. 1997;Smith and Boeke 1997). Silencing causes a more closed, inaccessible regional chromatin structure, as assayed by various probes of DNA accessibility (Loo and Rine 1994; Bi and Broach 1997). Even though expression of marker genes inserted into the rDNA is repressed, silencing of rDNA transcription itself may be more modest, as continued ribosome synthesis is essential for growth. The Sir proteins may also function in DNA repair by nonhomologous end-joining (NHEJ) (Tsukamoto et al. 1997; Boulton and Jackson 1998). In this regard, the Sir2/3/4 proteins and Ku relocalize from telomeres to sites of DNA breaks to aid in their repair by NHEJ (Fig.1A) (Martin et al. 1999; Mills et al. 1999). A primary role of the Sir complex at telomeres therefore may be to provide a reservoir of factors that can be mobilized for the immediate repair of DNA damage.