SUMMARY PARAGRAPH for HTA1
About yeast nucleosomes...
Chromatin is composed of arrays of nucleosomes, with each nucleosome comprising an octamer formed by two copies each of the H2A-H2B and H3-H4 heterodimers (8). In Saccharomyces cerevisiae, each of the canonical histones is encoded by two genes: H2A by HTA1 and HTA2, H2B by HTB1 and HTB2, H3 by HHT1 and HHT2, and H4 by HHF1 and HHF2. The eight genes are organized into four pairs of divergently-transcribed loci: HTA1-HTB1 and HTA2-HTB2, each encoding histone proteins H2A and H2B; and HHT1-HHF1 and HHT2-HHF2, each encoding histone proteins H3 and H4. As a result of this redundancy, deletion of any one histone locus does not cause lethality (9). The H3-H4 protein dimers interact via a four-helix bundle at the H3 C-termini, and the H2A-H2B dimers bind to the resulting central H3-H4 tetramer via a similar four-helix bundle interaction between the H2B and H4 C-termini (10). Approximately 150 bp of duplex DNA is wound onto the histone octamer as two turns of a negative superhelix (11). A single copy of the linker histone H1 (encoded by HHO1) binds between the superhelices at the site of DNA entry and exit. In some nucleosomes, the histone variant H2A.Z (encoded by HTZ1) is substituted for the canonical H2A in a wide, but nonrandom, genomic distribution, enriched in promoter regions as compared to coding regions (12). The positioning of nucleosomes along chromatin has been implicated in the regulation of gene expression, since the packaging of DNA into nucleosomes affects sequence accessibility (13). Nucleosomes prevent many DNA-binding proteins from approaching their sites (14, 15, 16), whereas appropriately positioned nucleosomes can bring discontiguous DNA sequences into close proximity to promote transcription (17).
About histone H2A...
Similar to other histones, H2A has a positively charged N-terminus (residues 1-21) that extends into the extranucleosomal space (18, 19). H2A is unique, however, in that its C-terminus (amino acids 121-132) also extends outside the nucleosome. Both termini contain modifiable residues with roles in different cellular processes, such as telomere position effect (TPE) and double-strand break (DSB) repair (18, 20).
Differential acetylation and deacetylation of lysines 5 and 8 appears to regulate telomeric silencing, and phosphorylation of threonine 126 is also required for proper TPE (18). Phosphorylation of serine 122 is necessary for survival in the presence of DNA damage, and also for sporulation, indicating a possible role in homologous recombination (20). Phosphorylation of serine 129 is crucial for G1 DNA damage checkpoint regulation, chromatin remodeling, and DSB repair through the recruitment of repair components (21, 22, 5, 23). Following DSB damage, Tel1p phosphorylates S129, which is situated within a conserved SQE consensus target motif, over a large domain encompassing many kilobases surrounding the DSB (21, 22, 5). The Rad9p checkpoint protein is recruited to this domain and phosphorylated by Mec1p, which activates the checkpoint kinase Rad53p and induces a G1 delay (21). Binding of the NuA4 nucleosomal histone acetyltransferase complex to phosphorylated H2A results in acetylation of H4, followed by recruitment of the SWR and INO80 chromatin remodeling complexes (24, 25). SWR catalyzes exchange of histone H2A for the variant H2A.Z (Htz1p), while INO80 displaces histone octamers and facilitates resection to form ssDNA at DSBs (26, 27, 28, 29, 30, 31, 32).
Deletion of either the N- or C-terminus of H2A reduces TPE efficiency, and deletion of the N-terminus or lack of T126 phosphorylation reduces non-homologous end joining (18). Mutants lacking phosphorylation at S122 exhibit impaired sporulation (20). Mutants lacking phosphorylation at S129 show defects in the G1 checkpoint response, including attenuated cell cycle delay, decreased Rad53p kinase activation, and reduced Rad9p phosphorylation and recruitment to damaged sites (21).
Last updated: 2007-05-31