Role Of Non Histone Proteins Acetylation On Cellular Function

Reversible acetylation of histone and nonhistone proteins play key role in maintaining cellular homeostasis. In this following section we shall discuss about the physiological significances of acetylation and deacetylation of different classes of nonhistone proteins.

2.1. Chromatin Dynamics and Transcription

Nonhistone chromatin proteins are integral structural components of the chromatin. The dynamicity of the chromatin is maintained by chromatin compaction leading to higher order structure formation and decompaction leading to an open chromatin that is a prerequisite for gene expression. There is a vast repertoire of nonhistone structural components viz. HMGs, HP1, MeCP2, Polycomb group of proteins, MENT complex, PARPs (McBryant et al., 2006), which are responsible for chromatin higher order structure formation. However, the acetylation dependent functional regulation is reported in few cases only. The HMGs are a set of nonhistone proteins that have direct influence in chromatin architecture. HMG group of proteins led to a decompaction of chromatin structure working in opposition to linker histone H1 (Catez et al., 2003). Acetylation of HMGs can significantly alter their dynamic interaction with chromatin. Acetylation of HMGN1 by p300 or HMGN2 by p300 or PCAF has distinct functional consequence (Bergel et al., 2000; Herrera et al., 1999). Acetylation of HMGN2 leads to a weak nucleosome binding ability (Herrera et al.,1999). Binding of HMGN1/N2 to the nucleosomal core particle also inhibits the acetylation of nucleosomal H3 by PCAF (Lim et al., 2005). However, HMGN (especially HMGN2) has been shown to act as chromatin specific transcriptional coactivator (Paranjape et al., 1995). Interestingly, acetylation of HMGN2 by p300 inhibits this coactivator activity (Banerjee and Kundu unpublished data). Presumably HMGN2, binding to the chromatin assist in the activator binding, which recruits the HAT. The active-HAT (complex) then acetylates the activators, promoter proximal histones, as well as HMGNs. These events may lead to the opening of chromatin for activator dependent transcriptional activation and also the removal of acetylated HMGN.

Enhanceosomes are nucleoprotein complexes, where specific regulatory proteins and activators interact to bring about the activation of specific genes. HMGA proteins are found to be integral components of enhanceosomes. Acetylation of HMGA by p300/CBP leads to enhanceosome disruption and hence transcrip-tional repression (Bergel et al., 2000). On the other hand acetylation of HMGA by PCAF leads to enhanceosome assembly and transcription activation (Herrera et al., 1999). This differential functional consequence can be attributed to the change in protein-protein and DNA-protein interaction brought about by the HATs. PARP-1 functions both as a structural component of chromatin and a modulator of chromatin structure through its intrinsic enzymatic activity. PARP1 is acetylated by p300/ CBP in vivo and acetylation is induced in response to inflammatory responses (Hassa et al., 2005). However PARPs acetylation and its effect on chromatin structure still needs to be understood.

Acetylation is known to regulate the function of several transcription factors by multiple ways, like effecting the DNA binding ability, protein protein interactions, protein half-life, and protein localization (Table 1). Acetylation causes enhanced sequence specific DNA binding for transcription factors like p53, E2F, EKLF, p50 and PC4 (Bode and Dong, 2004; Martinez-Balbas et al., 2000; Marzio et al., 2000; Chen and Bieker, 2004; Chen et al., 2004; Kumar et al., 2001, Table 1), where as it reduces DNA binding of certain factors like Foxo1, HMGI (Y), p65 (Matsuzaki et al., 2005)(Table 1). The ability to activate or repress the DNA binding ability depends on the site of acetylation. If the acetylation sites lie in DNA binding domain it repress the DNA binding and if they are adjacent to DNA binding domain, then it activates DNA binding (see Table 1).

p53 is a sequence specific DNA binding transcription factor known to maintain the cellular homeostasis. p53 function is directly correlated with its sequence specific DNA binding to the promoters of its regulatory genes. p53 C-terminal domain binds to its core DNA binding domain and prevents p53 DNA binding. p53 was the first sequence specific transcription factor known to be acetylated by p300/CBP (Gu and Roeder, 1997). Acetylation at specific lysine residues

Table 1. Biochemical and cellular functions of non-histone protein acetylation "Enhances-

DNA Binding-

•p53, E2F1, EKLF, P50, PC4, AML1, IRF, STAT3, SRY, ATA1, GATA1, GATA 2

^ Protein stability


Protein Protein-interaction

Protein localization

.Destabilizes-►HIF 1-a

Enhances-»-STAT3, AR, EKLF, Importin a


Nuclear Export "^P53, HMGB1




-Repression —►HMGI(Y), C myc, ER a, HIFI a Activates -*>p53, E2F, TDG


-►NEIL2, FEN1, Pol b in the C-terminus of p53 consequently activate DNA binding by neutralizing the positive charge and preventing its interaction with core DNA binding domain (Luo et al., 2004) (Fig. 2). While the acetyltransferases enhance p53 DNA binding ability, p53 dependant transactivation, deacetylases repress p53 dependant transcription. Mdm2 a well-known negative regulator of p53 suppresses p300-mediated acetylation by recruiting HDAC1 containing complex and that deacetylate p53 (Ito et al., 2002; Jin et al., 2002, Fig 2). However MDM2 is also a substrate of p300 and the acetylation of Mdm2 inhibits MDM2 mediated p53 degradation (Wang et al., 2004). SirT1, a NAD dependant deacetylase, deacetylates p53 and suppresses p53 dependant function in vivo (Vaziri et al., 2001, Fig 2). Inhibition of SirT1 by a small molecular inhibitor increases acetylation at Lysine 382 residue of p53 after different types of DNA damage in primary human mammary epithelial cells (Solomon et al., 2006). Therefore, it is quite evident that reversible acetylation of p53 is a key regulator of the p53 activity as a transcrip-tional regulator. However, the effect of p53 acetylation on its activation by other proteins (like HMGB1 or PC4) is yet to be elucidated. The tumor suppressor, p53, represses more number of genes than it activates (Kinzler and Vogelstein, 1996). To date no information is available regarding the role of post-translational modifications of p53 on its transcription repression activity.

Histone Proteins Function

Figure 2. Regulation of p53 function by acetylation / deacetylation: Under stresses conditions p53 gets phosphorylated, acetylated and consequently gets stabilized. Acetylated p53 has enhanced transcriptional ability leading to the activation several p53 responsive genes, which plays important roles in diverse cellular processes. Decateylation of p53 by SirT1 and HDAC1 down regulates p53 activity by enabling interaction with MDM2 followed by nuclear export and p53 degradation. (See Colour Plate 13.)

Figure 2. Regulation of p53 function by acetylation / deacetylation: Under stresses conditions p53 gets phosphorylated, acetylated and consequently gets stabilized. Acetylated p53 has enhanced transcriptional ability leading to the activation several p53 responsive genes, which plays important roles in diverse cellular processes. Decateylation of p53 by SirT1 and HDAC1 down regulates p53 activity by enabling interaction with MDM2 followed by nuclear export and p53 degradation. (See Colour Plate 13.)

Another important transcription factor that plays crucial role in cell cycle progression is E2F. p300/ CBP mediated acetylation at the N-terminus of E2F enhances its sequence specific DNA binding ability, which is correlated with the enhanced transcription from E2F responsive promoters. As expected the acetylation dependent effect could be reversed by HDAC1 mediated deacetylation (Martinez-Balbas et al., 2000; Marzio et al., 2000). There are several other non-histone factor acetyl transferase substrates like GATA1, CBP, Runxl and HMGB1 etc. Prototype transcription factor GATA 1 regulates hematopoiesis and autoregulates its own expression by self-association. GATA1 interacts with p300/CBP and the acetylation of GATA1 increases the transcriptional activity (Nishikawa et al., 2003). Mutations in acetylation sites present in GATA1 causes decreased transcriptional activity. Cyclic AMP response element binding protein is a substrate of CBP and the acetylation of CREB significantly elevates CREB/CBP mediated transcription. (Lu et al., 2001). RUNX1 gene is mutated in many human leukemia. Acetylation of RUNX1 by p300 increases its DNA binding ability and transcriptional activation (Yamaguchi et al., 2004).

Global transcriptional coactivator PC4 is known to get acetylated specifically by p300 but not PCAF and GCN5 in vitro and in vivo in humans (Kumar et al., 2001, Das and Kundu unpublished data). Acetylation of PC4 at least in the two-lysine residues, enhances its DNA binding ability. In the cell PC4 is present predominantly as a phospho-protein. Phosphorylation of PC4 was found to negatively regulate the acetylation, which is a rare example for any protein, which harbor both the posttranslational modifications (Kumar et al., 2001). Most of the cases, phosphorylation enhance (favor) the acetylation of proteins (Warnock et al., 2005). PC4 directly interact with p53 in vitro and in vivo and enhance the sequence specific DNA binding of p53 (Banerjee 2004). Furthermore, it also induces the expression of p53 responsive genes and thereby enhances the p53 dependent apoptosis. Since both p53 and PC4 gets acetylated it would be interesting to find out the role of reversible acetylation of these two proteins in the regulation of cellular homeostasis. However, the deacetylation pathway of PC4 is not known yet. Initial data suggest that PC4 gets partially deacetylated by HDAC1 (Swaminathan and Kundu unpublished data).

Histone chaperones are also a group of nonhistone proteins, which directly interact with core or linker histones and actively participate in the histone metabolism pathway (also see chapter on Histone Chaperone in Chromatin Dynamics by Jayasha et al.). Emerging evidences suggest that the acetylation of histones as well as chaperones are the key regulator of histone chaperone function. The H2A-H2B histone chaperone, NAP1 though is not an in vivo substrate for p300 acetylation, it is a functional component of the p300 coactivator, which indicate, that NAP1 may be a point of connection between chromatin and transcriptional coactivators (Shikama et al., 2000). Interestingly, it was found that indeed the acetylation of histones by p300 facilitates the transfer of H2A-H2B from nucleosomes to NAP1 (Ito et al., 2000). Presumably, this would help in the alteration of chromatin structure for transcrip-tional activation. At this juncture it was important to know what would happen if any chaperone, which is required for transcriptional activation gets acetylated. Recently we have found that p300 specifically acetylates human histone chaperone, Nucleophosmin (NPM1). Acetylation enhances its histone chaperone function and chromatin transcriptional activity (Swaminathan et al., 2005). NPM1 is a multifunctional nucleolar phosphoprotein. The level of nucleophosmin gets upregulated during various stress like UV rays, DNA damaging drug treatment, various disease conditions like acute myeloid leukemia, and glioblastoma multiforme (for further details see Chapter on Histone Chaperone in Chromatin Dynamics by Jayasha et al.).

Acetylation of p53, E2F and many other proteins not only activates their transcriptional activities but also half-life (Li et al., 2002; Martinez-Balbas et al., 2000). Apart from DNA binding, and protein half-life, acetylation also plays pivotal role in protein-protein interactions thereby cellular processes involved. However, the acety-lation of pRb regulates the specific interaction with E2F-1 (Markham et al., 2006). E2F activity is negatively regulated by its interaction with pRb, which recruits histone decetylase complexes and probably lead to the deacetylation of E2F.

CtBP (carboxyl-terminal binding protein) participates in regulating cellular development and differentiation by associating with a diverse array of transcriptional repressors. This family of protein plays crucial role in differentiation, apoptosis, oncogenesis and development (Corda et al., 2006). CtBP interacts with p300 bromodomain and inhibits its transcriptional activity. It also interacts with nuclear hormone receptor corepressor RIP140 and the acetylation of RIP140 inhibits its interaction with CtBP and thereby acts negatively for transcriptional repression (Vo et al., 2001). Acetylation of adenoviral protein E1A inhibits its interaction with CtBP and leading to alleviation of transcriptional repression mediated by CtBP. (Zhang et al., 2000).

In general, retroviral gene expression is regulated by chromatin dynamics of the host genome. For example upon integration, HIV genome forms nucleosomal structure and depends upon the host chromatin modifications for the viral gene expression (for details see chapter on Chromatin modifying enzymes and HIV gene expression by Quivy et al.,). Furthermore, the HIV1 Tat protein, crucial for viral replication and transcription gets acetylated by both p300/CBP and PCAF. The p300-mediated acetylation of Tat, enhances transcriptional coactivation and also enhances its binding to core histones (Ott et al., 1999; Deng et al., 2000). Site-specific acetylation of Tat differentially regulates its interacting partners like PCAF and cyclin T1 (Tagami et al., 2002). The multifunctional transcriptional activator NF-kB control the expression of several genes related to stress induced, immune, inflammatory responses and the HIV gene expression. The activity of NF-kB is negatively regulated by its interaction with IkB. Acetylation of NF-kB by p300/CBP inhibits its interaction with IkB and induces translocation of the factor to nucleus (Chen et al., 2004). Acetylation of NF-kB is regulated by the prior phosphorylation. The phospho-acetylated forms of NF-kB display enhanced transcriptional activity. Histone decateylase 3 (HDAC3) deacetylates NF-kB enabling it to bind IKB and causing its translocation in to cytoplasm (Chen et al., 2004).

Acetylation at lysine residues present in nuclear localization signal of proteins helps in nuclear retention. For example, acetylation regulates p53 subcellular localization by promoting p53 nuclear export (Kawaguchi et al., 2006, Fig 2). The other important instance is in the case of multifunctional non-histone chromatin protein HMGB1, where p300 mediated acetylation causes nuclear export and cytosolic accumulation. POP1 is a transcription factor mediates Wnt signaling pathway and plays crucial role in embryogenesis. Acetylation of POP1 inhibits nuclear export and increases nuclear import (Gay et al., 2003). HELA E box binding protein (HEB) has an important role in thymopoiesis and acetylation by HATs increases its nuclear retention and enhances its transcriptional activities. The orphan nuclear receptor SF-1 regulates the development and differentiation of steroidogenic tissues. Acetylation of SF1 by GCN5 regulates its transcriptional activity and stabilizes the protein. Inhibition of deacetylation using TSA increases SF1 mediated transcriptional activation and nuclear export of SF1 protein (Jacob et al., 2001). These examples clearly establish the fact that acetylation of nonhistone proteins is crucial for cell signaling.

DNA viruses can regulate the activity of cellular acetyltransferases and to effect cell cycle progression in support of virus replication. Viral infection mediated assembly of enhanceosome at IFN-B promoter requires HMGI (Y). CBP, PCAF are recruited to this complex and CBP mediated acetylation of HMG I (Y) decreases its DNA binding ability and causes enhanceosome disruption (Munshi et al., 2001). Autoacetylation of transcription factors is also one of the mechanisms in controlling the gene expression. Autoacetylation of acetyl transferases also regulates its activity. PCAF gets acetylated by itself and by p300 and the acetylation of PCAF enhances its acetyl transferase activity (Herrera et al., 1997). Autoacetylation of general transcription factor TFIIB strengthens its interaction with TFIIF (Choi et al., 2004) and thereby transcription suggesting the role of transcription factor auto acetylation in the regulation of transcription.

2.2. Cellular Processes

Cell cycle progression, apoptosis, DNA damage and DNA repair are cellular functions that are regulated by several mechanisms. One such important regulatory mechanism is posttranslational modification of histone and non-histone proteins. Myriad of reports have been shown that acetylation of non-histone proteins apart from histones, contributes in major to these processes.

2.2.1. Apoptosis

Apoptosis is physiological process of cell killing regulated by several families of proteins (divided as proapoptotic and antiapoptotic proteins) and their post translational modifications. Acetylation of p53 is very important for p53-mediated apoptosis. Acetylation of p53 at distinct sites regulates different cellular activities performed by p53. Acetylation at 373 position in p53 by p300/CBP leads to apoptosis where as acetylation at 320 residue by PCAF leads to cell cycle arrest (Knights et al., 2006). Under stressed conditions acetylation levels of p53 increases, which results in active form of p53. Acetylation of p53 is also controlled by deacetylases such as HDAC1, HDCA3, and hSIRTl. hSIRTl, HDAC2 interact with p53. Inhibitors of hSIRTl and HDAC2 enhance p53 acetylation and thereby p53 mediated apoptosis (Huang et al., 2005; Olaharski et al., 2005). p53 homologue, p73 also gets acetylated and activated in response to DNA damage and potentiates the p73 mediated apoptosis (Costanzo et al., 2002). The DNA end joining protein Ku70 prevents apoptosis by sequestering a proapop-totic protein Bax from mitochondria (Cohen et al., 2004). However, the acetylation of Ku70 disrupts its interaction with Bax and elevates Bax mediated apoptosis. On the other hand, Statl has been known to repress NF-kB mediated cell signaling. Acetylated Statl interacts with NF-kB thereby preventing its DNA binding ability, nuclear localization and finally expression of anti apoptotic genes (Kramer et al., 2006). These examples clearly indicate that acetylation of nonhi-stone proteins may induce or inhibit the apoptosis depending upon the protein and physiological status. However, detailed information from this area of research, would help to design therapeutic molecules that would activate apoptosis in the malignant cells.

2.2.2. Cell cycle progression

Crucial stages of cell cycle are generally controlled through transcriptional regulation of a subset of genes, which in turn regulated by acetylation/deacetylation of histone and non histone proteins. One of the notable examples is the regulation of C-myc gene expression and cell cycle progression. C-myc regulates the expression of several genes involved in growth promotion by associating with its DNA binding partner max. p300 associates with C-myc and helps in C-myc stabilization independent of p300 mediated acetylation where as C-myc acetylation increases its turnover (Faiola et al., 2005). Another cell cycle regulatory protein CyclinD1 plays key regulatory role during G1 phase and is over expressed in many cancers. Cyclin D1 interacts with PCAF and facilitates the association of ER and PCAF. Over expression of PCAF results in cyclinD1 dependent regulation of ER activity (McMahon et al., 1999). Interestingly, Cyclin D1 expression is down regulated by HDAC1 complex recruited to its promoter by SMAR1, a matrix attachment region binding proteins (Rampalli et al., 2005).

Nuclear receptor function is controlled by its acetylation similar to phospho-rylation. The androgen receptor (AR) is a nuclear hormone receptor superfamily member that conveys both trans repression and ligand-dependent trans-activation function. Activation of the AR leads to diverse cellular processes like secondary sexual differentiation in males and the induction of apoptosis by the JNK kinase, MEKK1. p300 acetylates androgen receptor and acetylation governs ligand sensitivity, cofactor recruitment and growth properties of receptors. Point mutations of the AR acetylation motif that abrogate acetylation reduce trans-activation by p300 without affecting the trans-repression function of the AR. The AR acetylation mutant was also defective in MEKK1-induced apoptosis, suggesting that the conserved AR acetylation site contributes to a pathway governing prostate cancer cellular survival (Fu et al., 2002). SirT1 physically interacts with AR and inhibits p300-mediated transactivation though its NAD dependent deacetylase activity. Estrogen receptor alfa regulates the ligand dependent and ligand independent transcription. p300 acetylates ER alfa and mutations in the acetylation sites dramatically enhanced the hormonal sensitivity and has no effect on MAPK signaling pathway suggesting acetylation may suppresses ligand sensitivity.

2.2.3. Oxidative stress

Oxidative Stress is a general term used to describe the steady state level of oxidative damage in a cell, tissue, or organ, caused by the reactive oxygen species (ROS) which are free radicals, reactive anions containing oxygen atoms. Oxidative stress and ROS have been implicated in disease states, such as Alzheimer's disease, Parkinson's disease, cancer, and aging. In addition to modulation of signaling processes and oxidation of cellular proteins and lipids, reactive oxygen species (ROS) induce multiple damages in both nuclear and mitochondrial genomes, most of which are repaired via the DNA base excision repair pathway. 8-Oxoguanine (8-oxoG), a major ROS product in the genome, is excised by 8-oxoG-DNA glyco-sylase (OGG1) and the resulting abasic (AP) site is cleaved by AP-endonuclease

(APE1) in the initial steps of repair (Szczesny et al., 2004). OGG1 is acetylated by p300 in vivo predominantly at Lys338/Lys341. Acetylation significantly increases OGGl's activity in the presence of AP-endonuclease by reducing its affinity for the abasic (AP) site product. The enhanced rate of repair of 8-oxoG in the genome by wild-type OGG1 but not the unacetylable K338R/K341R mutant. oxidative stress increases the acetylation of OGG1 by about 2.5-fold after with no change at the polypeptide level. OGG1 interacts with class I histone deacetylases, which is responsible for its deacetylation (Bhakat et al., 2004). This indicates towards a novel regulatory function of OGG1 acetylation in repair of its substrates in oxidatively stressed cells. Forkhead transcription factor, DAF-16, regulates genes that contribute both to longevity and resistance to various stresses in C. elegans. Members of the FOXO, mammalian homologs of DAF-16, also regulate genes related to stress resistance, such as GADD45. Acetylation of FOXO4, by the transcriptional coacti-vator p300, counteracted transcriptional activation of FOXO4 by p300 (Kobayashi et al., 2005). In contrast, mammalian SIRT1 (a class III histone deacetylase) was found to bind to FOXO4, catalyze its deacetylation in an NAD-dependent manner, and thereby increase its transactivation activity (Horst et al., 2004). In response to oxidative stress, FOXO accumulates within the nucleus and induces GADD45 expression. FOXO-mediated GADD45 induction is markedly impaired in the cell, which depleted SIRT1 expression by RNA-interference (Kobayashi et al., 2005). These results indicate that mammalian SIRT1 plays a pivotal role for FOXO function via NAD-dependent deacetylation in response to oxidative stress, and thereby may contribute to cellular stress resistance and longevity.

Heat shock protein, Hsp90 is a well known stress-induced protein with a more general housekeeping function. The emerging significance of Hsp90 in both normal and oncogenic signaling highlights the need to understand how Hsp90 is regulated. It is known that Hsp90 becomes transiently acetylated upon GR activation after ligand stimulation, which might allow the conversion of GR-Hsp90 from a stable complex into a dynamic one thereby enabling GR to enter the nucleus for transcrip-tional activation. Subsequent deacetylation by HDAC6 would then allow Hsp90 to re-enter the productive chaperone complex (Murphy et al., 2005). Acetylation of molecular chaperones might play a role in the dynamic reorganization of chaperone complexes in response to "oncogenic stress" which might be induced by high demand for "growth and proliferation"-associated signaling (Kovacs et al., 2005). Under this scenario, HDAC6 may then be required for robust Hsp90 activity by regenerating deacetylated Hsp90 and thereby ensuring effective cell signaling.

2.2.4. DNA damage and repair

Acetylation levels of histone and non-histone proteins are regulated upon DNA damage. Retinoblastoma protein pRb controls G1-S phase transition and phospho-rylation of pRb regulates it function. DNA damage induced acetylation of pRb near the phosphorylation sites prevents it phosphorylation and keep pRb in active form thereby leading to growth repression. DNA damage dependant association of E2F with p300 not only accumulates Ac-E2F but also subsequent ubiquitinated E2F. However p300 induced ubiquitination is not dependant on pRb (Galbiati et al., 2005). In another case, DNA damage induced phosphorylation of p53 at ser 33 and 37 increases p53 affinity for p300 and PCAF thus promoting acetylation of carboxy-terminal sites including Lys-382 (by p300) and Lys-320 (by PCAF)(Sakaguchi et al., 1998). Acetylation at both these sites causes conforma-tional change and enhances sequence specific DNA binding ability of p53. p53 homologue p73 also gets accumulated during DNA damage and half-life of p73 is partially dependant on C-ABL kinase (Gong et al., 1999). C-ABL is required for p300 mediated acetylation of p73 upon genotoxic insult and enhances p73 dependant apoptosis. Like p53 both phosphorylation and acetylation of p73 contributes to its function under DNA damaging condition (Costanzo et al., 2002). The ATM protein kinase is a critical intermediate in a number of cellular responses to ionizing irradiation (IR) and possibly other stresses. DNA damage induces rapid acetylation of ATM by TIP60. Inhibition of Tip60 blocks the ATM dependant phosphorylation of p53 and Chk2 further sensitizes the cells to ionizing radiation (Sun et al., 2005).

Werner's syndrome is a result of mutation in WRN gene, which encodes DNA helicase. The translocation of WRN from nucleolus into nucleoplasmic foci is significantly enhanced by its acetylation by p300 under DNA damaging condition (Blander et al., 2002). DNA pol ß is key protein involved in Base excision repair. p300 acetylates polß and severely impairs its activity implying the role of acetylation in Base Excision Repair (Hasan et al., 2002). Another DNA repair protein DNA glycosylase NEIL2 gets acetylated by p300 and the acetylation inhibits its repair activity (Bhakat et al., 2004). Thymine DNA Glycolsylase (TDG) initiates repair of G/T and G/U mismatches by removing thymine and uracil residues. TDG associates with CBP/p300 and results in transcriptional activation by CBP. p300/CBP mediated acetylation of TDG leads to disruption of CBP from DNA ternary complex and also regulates recruitment of repair endonuclease APE (Lucey et al., 2005). Above observation strongly argues for the potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability.

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