Structure and function of the BAH-containing domain of Orc1p in epigenetic silencing

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Abstract
The N‐terminal domain of the largest subunit of the Saccharomyces cerevisiae origin recognition complex (Orc1p) functions in transcriptional silencing and contains a bromo‐adjacent homology (BAH) domain found in some chromatin‐associated proteins including Sir3p. The 2.2 Å crystal structure of the N‐terminal domain of Orc1p revealed a BAH core and a non‐conserved helical sub‐domain. Mutational analyses demonstrated that the helical sub‐domain was necessary and sufficient to bind Sir1p, and critical for targeting Sir1p primarily to the cis ‐acting E silencers at the HMR and HML silent chromatin domains. In the absence of the BAH domain, ∼14–20% of cells in a population were silenced at the HML locus. Moreover, the distributions of the Sir2p, Sir3p and Sir4p proteins, while normal, were at levels lower than found in wild‐type cells. Thus, in the absence of the Orc1p BAH domain, HML resembled silencing of genes adjacent to telomeres. These data are consistent with the view that the Orc1p–Sir1p interaction at the E silencers ensures stable inheritance of pre‐established Sir2p, Sir3p and Sir4p complexes at the silent mating type loci.