Meleah Hickman

Promoter-specific repression and regional, long-range spreading of silencing factors may seem like two distinct mechanisms for transcriptional gene repression, but emerging evidence suggests that they can be related. In Saccharomyces cerevisiae the cryptic mating type loci are subject to long-range silencing mediated by the Sir complex, whereas mid-sporulation genes are repressed by the promoter specific Sum1 complex. These complexes utilize the histone deacetylases Sir2p and Hst1p respectively, which are known paralogs originating from an ancient whole-genome duplication. I have investigated the evolution of the HST1-SIR2 duplicate gene pair, and by extension the Sir and Sum1 complexes, from two complementary perspectives, the duplicated and non-duplicated contexts, by using the model organism S. cerevisiae and the emerging model organism Kluyveromyces lactis, which diverged from S. cerevisiae prior to the duplication event. I have previously shown (Hickman and Rusche, 2007) that in S. cerevisiae Sir2p can substitute for Hst1p in its absence by interacting with Sum1p, the normal partner of Hst1p. Furthermore, the existence of two distinct protein interaction domains for the Sir and Sum1 complexes was revealed through the analysis of a chimeric Sir2–Hst1 molecule. Moreover, the non-duplicated histone deacetylase from K. lactis has both Hst1p- and Sir2p-like functions when expressed in an S. cerevisiae hst1Δ sir2Δ background. From these results, I have postulated that the SIR2-HST1 duplicate gene pair subfunctionalized. I am currently investigating whether distinct Sir- and Sum1-like repression mechanisms are employed by K. lactis, in which only a single Sir2/Hst1 deacetylase exists. I am characterizing deletion phenotypes as well as the associations of proteins with genomic loci and proposed interacting partners to assess Sir2p-mediated repression in K. lactis.

Publications

Hickman, M.A. and Rusche L.N. (2007) “Substitution as a mechanism for genetic robustness: The duplicated deacetylases Hst1p and Sir2p in Saccharomyces cerevisiae.” PLOS Genet 3:e126.

Hickman, M.A. and Rusche L.N. (2007) “Evolution of silencing at the mating-type loci in hemiascomycetes” in Sex in Fungi: molecular determination and evolutionary implications. Heitman, Casselton, and Kronstad editors, ASM press.