Figure 8.

Models for Sir2p silencing function and the involvement of distinct Sir2p-containing complexes in HM/telomeric and rDNA silencing. (A) Wild-type Sir2p function. Sir2p interacts with itself and Sir3p/Sir4p in a complex (Moazed and Johnson, 1996; Holmes et al., 1997; Moazed et al., 1997; Strahl-Bolsinger et al., 1997) and localizes to and silences the HM loci and telomeres (Hecht et al., 1996; Gotta et al., 1997; Strahl-Bolsinger et al., 1997). Because Sir3p and Sir4p are not required for rDNA silencing (Smith and Boeke, 1997), a second Sir2p-containing complex involving one or more unidentified factors (I and II) localizes to and silences the rDNA. Single silencing complexes are shown for simplicity, although it is believed that numerous complexes, perhaps in multimeric forms, localize to and silence each of the loci. (B) Sir2-hSir2A chimera function. The chimeras continue to dimerize or oligomerize and interact with other silencing factors. They localize to the HM loci to silence them but fail to localize properly to the telomeres and rDNA, leading to a loss of silencing. In the presence of wild-type Sir2p, Sir2p-chimera heteromers form. These heteromeric forms continue to interact with HM and telomeric silencing factor(s), e.g., Sir3p and Sir4p, and titrate them, leading to a loss of silencing at these loci. On the other hand, the Sir2p-chimera heteromers interact correctly with rDNA silencing factors (I and II) and localize subnucleolarly, leading to rDNA silencing function. Although Sir2p and the Sir2p-hSir2A chimeras are diagrammed as dimers based on wild-type Sir2p’s demonstrated ability to interact with itself (Moazed et al., 1997), the functional form of Sir2p and its variants has yet to be determined. Thus, they may function as higher-order multimers, dimers, or even monomers. Furthermore, the functional form of the Sir2-hSir2A chimeras may differ from that of wild-type Sir2p.