Model for Sir3 as a determinant of telomere clustering. Schematic representation of yeast telomeres in different conditions (endogenous/overexpressed Sir3 and wild-type/mutant strains). (A) When Sir3 is expressed at endogenous levels, the Sir2–3–4 trimeric complex is recruited to the TG repeats by Rap1 and spread over 2–3 kb away from the telomere (TEL) ends (Rusche et al., 2003; Moazed et al., 2004). We propose that Sir3–Sir3 interactions promote trans-interaction between Sir3-bound telomeres leading to the grouping of three to five telomeres. (B) Upon Sir3 overexpression, Sir3 (but not Sir2 and Sir4) spreads further away from telomere ends (15 kb; Figs. 5 D and 6 B; Hecht et al., 1996; Strahl-Bolsinger et al., 1997; Katan-Khaykovich and Struhl, 2005), generating extended silent chromatin and long arrays of Sir3 proteins in subtelomeric regions. The additional pool of Sir3 bound to telomere ends and subtelomeric regions increases telomere–telomere (Telo/Telo) interactions leading to the formation of telomere hyperclusters. (C) In the absence of Sir2, Sir3 is not correctly recruited to the TG repeats and, thus, cannot mediate telomere–telomere interactions. (D) However, nonacetylable Sir3 is well recruited at the TG repeats independently of Sir2 and mediates telomere hyperclustering when overexpressed through Sir3–Sir3 interactions occurring only at the very end of telomeres. CEN, centromere. TPE, telomeric position effect.