<P> H3 and H4 histone proteins are the primary targets of HATs, but H2A and H2B are also acetylated in vivo . Lysines 9, 14, 18, and 23 of H3 and lysines 5, 8, 12, and 16 of H4 are all targeted for acetylation . Lysines 5, 12, 15, and 20 are acetylated on histone H2B, while only lysines 5 and 9 have been observed to be acetylated on histone H2A . With so many different sites for acetylation, a high level of specificity can be achieved in triggering specific responses . An example of this specificity is when histone H4 is acetylated at lysines 5 and 12 . This acetylation pattern has been seen during histone synthesis . Another example is acetylation of H4K16, which has been associated with dosage compensation of the male X chromosome in Drosophila melanogaster . </P> <P> Histone modifications modulate the packing of chromatin . The level of packing of the DNA is important for gene transcription, since the transcriptional machinery must have access to the promoter in order for transcription to occur . Neutralization of charged lysine residues by HATs allows for the chromatin to decondense so that this machinery has access to the gene to be transcribed . However, acetylation is not always associated with enhanced transcriptional activity . For instance, acetylation of H4K12 has been associated with condensed and transcriptionally inactive chromatin . In addition, some histone modifications are associated with both enhanced and repressed activity, in a context - dependent manner . </P> <P> HATs act as transcriptional co-activators or gene silencers and are most often found in large complexes made up of 10 to 20 subunits, some of which shared among different HAT complexes . These complexes include SAGA (Spt / Ada / Gcn5L acetyltransferase), PCAF, ADA (transcriptional adaptor), TFIID (transcription factor II D), TFTC (TBP - free TAF - containing complex), and NuA3 / NuA4 (nucleosomal acetyltransferases of H3 and H4). These complexes modulate HAT specificity by bringing HATs to their target genes where they can then acetylate nucleosomal histones . Some HAT transcriptional co-activators contain a bromodomain, a 110 - amino acid module that recognizes acetylated lysine residues and is functionally linked to the co-activators in the regulation of transcription . </P> <P> The ability of histone acetyltransferases to manipulate chromatin structure and lay an epigenetic framework makes them essential in cell maintenance and survival . The process of chromatin remodeling involves several enzymes, including HATs, that assist in the reformation of nucleosomes and are required for DNA damage repair systems to function . HATs have been implicated as accessories to disease progression, specifically in neurodegenerative disorders . For instance, Huntington's disease is a disease that affects motor skills and mental abilities . The only known mutation that has been implicated in the disease is in the N - terminal region of the protein huntingtin (htt). It has been reported that htt directly interacts with HATs and represses the catalytic activity of p300 / CBP and PCAF in vitro . HATs have also been associated with control of learning and memory functions . Studies have shown that mice without PCAF or CBP display evidence of neurodegeneration . Mice with PCAF deletion are incompetent with respect to learning, and those with CBP deletion seem to suffer from long - term memory loss . The misregulation of the equilibrium between acetylation and deacetylation has also been associated with the manifestation of certain cancers . If histone acetyltransferases are inhibited, then damaged DNA may not be repaired, eventually leading to cell death . Controlling the chromatin remodeling process within cancer cells may provide a novel drug target for cancer research . Attacking these enzymes within cancer cells could lead to increased apoptosis due to high accumulation of DNA damage . One such inhibitor of histone acetyltransferases is called garcinol . This compound is found within the rinds of the garcinia indica fruit, otherwise known as mangosteen . To explore the effects of garcinol on histone acetyltransferases, researchers used HeLa cells . The cells underwent irradiation, creating double - strand breaks within the DNA, and garcinol was introduced into the cells to see if it influenced the DNA damage response . If garcinol is successful at inhibiting the process of non-homologous end joining, a DNA repair mechanism that shows preference in fixing double - strand breaks, then it may serve as a radiosensitizer, a molecule that increases the sensitivity of cells to radiation damage . Increases in radiosensitivity may increase the effectiveness of radiotherapy . </P>

Mutants defective for a histone acetyltransferase which adds acetyl groups to histones will