Mutagenesis of pairwise combinations of histone amino-terminal tails reveals functional redundancy in budding yeast

Abstract

A large body of literature provides compelling evidence for the role of evolutionarily conserved core histone residues in various biological processes. However, site-directed mutagenesis of individual residues that are known to be sites of posttranslational modifications often does not result in clear phenotypic defects. In some cases, the combination of multiple mutations can give rise to stronger phenotypes, implying functional redundancy between distinct residues on histones. Here, we examined the “histone redundancy hypothesis” by characterizing double deletion of all pairwise combinations of amino-terminal tails (N-tails) from the four core histones encoded in budding yeast. First, we found that multiple lysine residues on the N-tails of both H2A and H4 are redundantly involved in cell viability. Second, simultaneous deletion of N-tails from H2A and H3 leads to a severe growth defect, which is correlated with perturbed gross chromatin structure in the mutant cells. Finally, by combining point mutations on H3 with deletion of the H2A N-tail, we revealed a redundant role for lysine 4 on H3 and the H2A N-tail in hydroxyurea-mediated response. Altogether, these data suggest that the N-tails of core histones share previously unrecognized, potentially redundant functions that, in some cases are different from those of the widely accepted H2A/H2B and H3/H4 dimer pairs.

A Highly Conserved Region within H2B Is Important for FACT To Act on Nucleosomes

“…4C). In contrast, deletion of amino acids 1 to 32 of H2B did not result in HU sensitivity (46). Collectively, our phenotypic analyses suggests that the HBR domain may be important for FACT activity and that residues located between 32 and 37 in the H2B tail are particularly important for this function.…”

Anti‐cancer drug KP1019 modulates epigenetics and induces DNA damage response in Saccharomyces cerevisiae

“…Upon multiple point mutations (H3K4,9,14,18,23,27 to Q) as well as H4K5,8,12,16 to Q) more severe growth defect was observed. Histone tails plays crucial role in maintaining nucleosome structure [26,27]; the enhanced sensitivity showed by histone tail mutants for KP1019 suggest that KP1019 exhibits its effect by further destroying nucleosome structure in these mutants.…”

High-resolution mapping of H4K16 and H3K23 acetylation reveals conserved and unique distribution patterns inArabidopsisand rice

“…Many acetylated residues act coordinately and the combined effect ultimately dictates the functional outcome. 25 For example, acetylation at K5, K8, and K12 of H4 are redundant with each other for nucleosome assembly and transcription. 26 Only the combined mutations in H4 K5, K8, and K12 residues exhibit accumulative impacts on gene expression levels, whereas the individual mutation has a negligible effect on transcription.…”