Program in Gene Function and Expression
Amino Acid Sequence; Animals; Catalytic Domain; Crystallography, X-Ray; Enzyme Activation; Histone Acetyltransferases; Histones; Kinetics; Models, Molecular; Molecular Chaperones; Molecular Sequence Data; Multiprotein Complexes; Protein Structure, Tertiary; Recombinant Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Static Electricity; Substrate Specificity; Xenopus Proteins; Xenopus laevis
Genetics and Genomics
Histone acetylation and nucleosome remodeling regulate DNA damage repair, replication and transcription. Rtt109, a recently discovered histone acetyltransferase (HAT) from Saccharomyces cerevisiae, functions with the histone chaperone Asf1 to acetylate lysine K56 on histone H3 (H3K56), a modification associated with newly synthesized histones. In vitro analysis of Rtt109 revealed that Vps75, a Nap1 family histone chaperone, could also stimulate Rtt109-dependent acetylation of H3K56. However, the molecular function of the Rtt109-Vps75 complex remains elusive. Here we have probed the molecular functions of Vps75 and the Rtt109-Vps75 complex through biochemical, structural and genetic means. We find that Vps75 stimulates the kcat of histone acetylation by approximately 100-fold relative to Rtt109 alone and enhances acetylation of K9 in the H3 histone tail. Consistent with the in vitro evidence, cells lacking Vps75 showed a substantial reduction (60%) in H3K9 acetylation during S phase. X-ray structural, biochemical and genetic analyses of Vps75 indicate a unique, structurally dynamic Nap1-like fold that suggests a potential mechanism of Vps75-dependent activation of Rttl09. Together, these data provide evidence for a multifunctional HAT-chaperone complex that acetylates histone H3 and deposits H3-H4 onto DNA, linking histone modification and nucleosome assembly.
DOI of Published Version
Nat Struct Mol Biol. 2008 Sep;15(9):948-56. Link to article on publisher's website
Nature structural and molecular biology
Berndsen, Christopher E.; Tsubota, Toshiaki; Lindner, Scott E.; Lee, Susan; Holton, James M.; Kaufman, Paul D.; Keck, James G.; and Denu, John M., "Molecular functions of the histone acetyltransferase chaperone complex Rtt109-Vps75" (2008). Program in Gene Function and Expression Publications and Presentations. 88.