Remodelling chromatin on a global scale: a novel protective function of p53

Simon J. Allison1 and Jo Milner

YCR P53 Research Group, Department of Biology, University of York, York YO10 5DD, UK

1 To whom correspondence should be addressed Email: sja13{at}york.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 
The tumour suppressor p53 has an essential role in maintaining the genomic integrity of the mammalian cell. This is achieved in part through its function as a transcription factor enabling it to induce either growth arrest or apoptosis in response to cellular stress. Changes in gene expression commonly require localized chromatin remodelling and p53 is known to interact in vivo with a variety of transcriptional co-activators and co-repressors with intrinsic histone modifying activities. Here we examine the links between p53 and chromatin structures associated with (i) transcriptional regulation of gene expression, (ii) with DNA repair as part of the process of nucleotide excision repair and (iii) with histone modifications which impact upon chromosomal condensation and ploidy.

Abbreviations: CPD, cyclobutane pyrimidine dimers; GGR, global genomic repair; NER, nucleotide excision repair


    Introduction
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 
The packaging of DNA into chromatin is a major obstacle to transcription as well as to DNA repair, recombination and replication (1). Chromatin remodelling is necessary to allow such processes to proceed and may be defined as a discernible alteration in chromatin structure that results in a change in the accessibility of a region of DNA. This encompasses changes induced by ATP-dependent remodelling complexes that can alter nucleosomal positioning, and post-translational modification of nucleosomal histones, which may alter the interactions between histones and the DNA (2,3). Post-translational histone modification may also play a role in chromatin remodelling indirectly through the specific recruitment of non-histone proteins such as ATP-dependent remodelling complexes to chromatin (4,5). The N-termini of the core histones are subject to a plethora of site-specific modifications including acetylation, methylation and phosphorylation (5). The significance of these modifications can vary between the different histones. For example, modification of the histone H3 has critical roles in heterochromatin and euchromatin formation (6), global chromatin condensation for mitosis (711), and chromatin remodelling for transcription and repair (5,12,13).

The tumour suppressor p53 has crucial roles in transcription, DNA repair and recombination (14). Here we discuss the links between p53 and chromatin structures associated with (i) transcriptional regulation of gene expression, (ii) with DNA repair as part of the process of nucleotide excision repair (NER) and (iii) with histone modifications, which impact upon chromosomal condensation and ploidy.


    p53 transcriptional regulation: a role for local chromatin remodelling
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 
Although euchromatin is transcriptionally competent, access of the transcriptional machinery to the DNA is severely restricted and transcription of genes located within euchromatin still requires local chromatin remodelling in order to proceed. The susceptibility of different genes to chromatin repression can vary considerably, however, depending upon factors such as the exact positioning of nucleosomes over the gene promoter and the ability of transcription factors to compete with histones for binding DNA (1,15). Consequently, the contribution of chromatin remodelling to regulation of gene expression can also differ drastically between genes.

A number of transcriptional co-activators and co-repressor complexes that bind p53 in vivo possess histone-modifying activities (1620) suggesting that targeted chromatin remodelling may be important for p53 function as a transcription factor. Moreover, in several cases the ability of a protein to act as a transcriptional co-activator or co-repressor has been shown to be dependent upon its enzymatic activity (21,22). However, histone acetyltransferases and histone deacetylases also target non-histone proteins for acetylation/deacetylation and, interestingly, such targets include p53 (1619,23,24). p53 is regulated by multiple post-translational modifications, including acetylation at a number of sites in its C-terminus (19,23,24). The co-activator and HAT p300 directly acetylates p53 at several lysine residues and acetylation has been reported to affect aspects of p53 function including DNA-binding (19,23,24), stability (25,26) and subcellular localization (27,28). Since p53 is a substrate for HATs and HDACs (1619,2326) it is quite likely that changes in p53-dependent transcription upon recruitment of these activities may not necessarily be due to changes in histone acetylation. A number of studies have addressed this issue directly and for some p53 target genes histone modification rather than modification of p53 is important for p53-dependent changes in gene expression (20,2931).

p53 can activate or repress transcription of a variety of cellular genes (32,33). p53-induced growth arrest seems to be mediated by transactivation of the p21 gene and several independent studies have sought to understand the mechanisms by which p53 regulates p21 transcription. Using a reconstituted in vitro transcription system with a chromatin-assembled p21 promoter, Epsinosa and Emerson found that the ability of p53 and p300 to activate p21 transcription is dependent upon cooperation to overcome the repressive effects of chromatin packing rather than acetylation of p53 by p300 (29). Chromatin immunoprecipitation experiments suggest that p53 recruits p300 to the p21 promoter thereby enabling targeted acetylation of chromatin-assembled core histones H2A, H2B, H3 and H4 (29).

Barlev and colleagues investigated how acetylation of p53 increases transcription of p21 in vivo (30). Following gamma irradiation they used chromatin immunoprecipitation to analyse the effects of p53 acetylation status on the association of p53 and of non-acetylatable p53 mutants with the endogenous p21 promoter (30). Consistent with the results of Epsinosa and Emerson, acetylation of p53 had no discernible effect on p53 binding to the endogenous p21 promoter. Exploring other possibilities, they found that acetylation of p53 promotes the association of the co-activators CBP and TRRAP with the p21 promoter (30). While CBP has intrinsic HAT activity (34), TRRAP is a component of multiple co-activator complexes with HAT activity including PCAF, TFTC, STAGA and Tip60 complexes (35,36). Recruitment of CBP and TRRAP by acetylated p53 correlated with elevated levels of acetylated H3 and H4 at the endogenous p21 promoter (30). In another study, a variety of p53 mutants expressed in stable cell lines were analysed for their ability to activate endogenous p21 transcription (37). While ChIP analysis revealed that the abilities of most of the mutants to bind to the p21 promoter was equivalent to that of wild-type p53, differences in their ability to activate transcription correlated directly with the extent of histone acetylation and levels of p300/CBP at the p21 promoter (37). In further support of the importance of chromatin remodelling in p53-mediated regulation of p21 transcription, Lagger et al. have discovered recently that p53 and the histone deacetylase HDAC1 are antagonistic regulators of p21 gene expression in vivo and that p53 can displace HDAC1 from the p21 promoter (38). Other transcriptional targets of p53 include mdm2. Here transcriptional activation is dependent on recruitment of TRRAP, correlating with increased histone acetylation suggesting that chromatin remodelling is also important for p53-dependent regulation of mdm2 transcription (31).

p53 also interacts with histone deacetylase complexes in vivo and work by Murphy et al. indicates that such interactions may be important for transcriptional repression by p53 (20). p53 recruits the transcriptional co-repressor mSin3a, which binds HDAC1, to the endogenous Map4 promoter, and this was found to correlate with histone deacetylation and reduced transcription (20). The histone deacetylase inhibitor trichostatin A abrogated the ability of p53 to repress transcription of the p53 target genes Map4 and stathmin (20).

Several subunits of the ATP-dependent remodelling complex SWI/SNF have also been shown to bind p53 and p53 can recruit hSNF and hBRG1 to the endogenous p21 promoter in vivo (39). Moreover, whilst over-expression of hSNF5 and BRG1 stimulated p53-dependent transcription of a reporter construct, dominant-negative forms of hSNF5 and BRG1 repressed transcription, p53-induced growth arrest and apoptosis (39).

It is apparent from these and other studies that regulation of local chromatin structure by p53, mediated through the varying actions of histone deacetylases, HATs and ATP-dependent remodelling complexes, is important for p53 function as a transcription factor. This is summarized in Figure 1, which shows a schematic of both transcriptional repression and transcriptional activation by p53 through local changes in chromatin structure. There is evidence that the mechanisms by which p53 activates or represses transcription may differ for different genes and that chromatin remodelling may be more important for changes in gene expression at some genes than others (31,40). The majority of studies have focused on the p21 gene and further work is required to look at the relative contribution of chromatin remodelling to p53-mediated changes in transcription at different p53 target genes.



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Fig. 1. Schematic showing examples of p53-dependent transcriptional regulation by local chromatin remodelling. (A) Transcriptional repression by p53 through recruitment of histone deacetylase activity and targeted core histone deacetylation at the Map 4 promoter (20). (B) p53 transcriptional activation at the p21 promoter mediated by displacement of HDAC1 (38), recruitment of the histone acetyltransferases p300 (29), CBP and TRRAP (30), targeted histone acetylation (29,30) and nucleosomal remodelling by ATP-dependent remodelling components hSNF5 and hBRG1 (39).

 

    Global chromatin remodelling for repair—a discrete p53 function
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 
The mammalian genome is prone to bombardment by a multiplicity of genotoxic insults as well as naturally occurring errors that need to be repaired. Amongst the most common forms of DNA damage are bulky DNA lesions such as cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts caused by UV-irradiation and other environmental carcinogens (41). These types of lesions are eliminated by NER, which comprises of two subpathways: transcription-coupled repair (TCR), which removes lesions from actively transcribed regions of the genome, and global genomic repair (GGR), which erases damage in non-transcribed regions (41). Efficient detection of these lesions requires chromatin relaxation (4245) and for TCR the ‘opening’ of chromatin by passage of the RNA polymerase along its template seems sufficient (45). For GGR global chromatin relaxation is required to allow detection of lesions throughout the genome (4345).

Although it is well documented that efficient NER requires p53 (46) its exact role has been difficult to define. Significantly, NER reconstituted in vitro with naked DNA has no requirement for p53 (47) but p53 is necessary for efficient NER in its natural context of chromatin and notably only for GGR (48,49). Moreover, the effect of p53 on the efficiency of GGR is much greater for CPDs than 6-4 photoproducts (48,49). CPDs are often located within nucleosomes and are thus much more dependent on chromatin relaxation for their repair than 6-4 photoproducts, which are only found in linker DNA (50). Together the data are clearly suggestive that p53 may function in NER by facilitating access to the chromatin for GGR. Using microscopy Rubbi and Milner asked if p53 can induce global chromatin relaxation for GGR and demonstrated that p53 is required for global chromatin relaxation induced by UV-irradiation (Figure 2) (43). Interestingly, the UV dose of 4 J/m2 used in this study is half the minimum dose necessary to activate p53 as a transcription factor (5153). This suggests that p53-dependent global chromatin relaxation is due to transcription-independent effects of p53. Furthermore, xeroderma pigmentosum cells deficient in p48, XPC or XPA all showed normal UV-induced global chromatin relaxation for GGR (43) thus demonstrating that the p53 requirement for global chromatin relaxation is not mediated by p48 or XPC transcriptional targets of p53. Under conditions in which p53 is activated as a transcription factor it is likely that p53 also has additional roles in NER (and perhaps chromatin accessibility) through the transcriptional induction of repair factors such as p48 and XPC (5457). Recent work from Ford and colleagues has shown that p48 can rapidly co-localize with CPD-containing foci following localized UV-irradiation and that p48 facilitates localization of XPC at such foci, leading to the suggestion that p48 may remodel chromatin thereby enabling the recognition of CPDs by XPC (56,57). Here it is important to distinguish between chromatin relaxation and chromatin remodelling, and to note that p48 is dispensable for p53-dependent chromatin relaxation (43) (see above) but may facilitate chromatin remodelling (56,57).



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Fig. 2. Schematic of p53-induced global chromatin relaxation in response to UV-irradiation. This allows access of the repair machinery to the DNA lesions for GGR. Recruitment of p300 and p53-dependent acetylation of lysine 9 of histone H3 may be involved in the ability of p53 to induce global chromatin relaxation but it is likely additional histone acetylation and other factors are also required (see text and ref. 43).

 
The histone deacetylase inhibitor trichostatin A overcomes the requirement for p53 suggesting that p53 may induce global chromatin relaxation through changes in histone acetylation (43). Following UV irradiation, histone acetylation increases (58), moreover, by comparison of p53+/+ and p53–/– cells and selective depletion of functional p53 by antibody microinjection Rubbi and Milner showed that UV-induced acetylation at lysine 9 of histone H3 is p53-dependent (43). The histone acetyltransferase p300 co-localizes with p53 to sites of NER and inhibition of p300 by antibody microinjection inhibits NER suggesting that p53-dependent recruitment of p300 HAT activity may be mechanistically involved in the ability of p53 to induce global chromatin relaxation (43).

It is also worth considering what happens after DNA repair. Clearly, there is a need to restore the chromatin to its original state of condensation, which will help protect the genome from incurring further damage. The transient nature of the relaxed chromatin state is indicated by the temporal profile of histone acetylation post-UV irradiation (43,58,59). It will be interesting to see whether p53 has an active role in chromatin condensation once repair is complete.


    p53 and histone modification—a complex affair
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 
Local, p53-dependent changes in histone acetylation have been observed at the promoters of a number of p53 target genes (20,2931,37,38,6062). The demonstration that p53 can induce global alterations in chromatin structure raised the possibility that p53 might influence histone modification on a global scale. Focusing upon modification of histone H3 because of its central role in local and global chromatin remodelling (59,12), we compared the pattern of modification at specific residues of H3 in isogenic clones of human p53+/+ and p53–/– cells. Since there is a general increase in histone acetylation following UV treatment (58) we were particularly interested to see whether other lysine residues of histone H3 in addition to K9 were similarly acetylated in response to UV irradiation. In contrast to K9, levels of acetylated K18 of histone H3 did not change in response to UV-irradiation (59). However, p53 did facilitate a rise in acetylated K14 levels (59). Our results demonstrate that p53, directly or indirectly, has site-specific effects on histone H3 acetylation in response to UV-irradiation and it will be interesting to see how these changes are mediated and if they contribute to p53-induced global chromatin relaxation for GGR. With the recent advances in siRNA technology it should be possible to confirm the effects of p53 upon histone H3 modification already observed in isogenic clones of human p53+/+ and p53–/– cells. RNA interference should also allow examination of p53 effects in a range of cell types of wild-type or mutant p53 background for which isogenic clones are not yet available.

The UV dosage of 10 J/m2 used in this study should also be sufficient to activate p53 as a transcription factor so these site-specific effects on histone H3 acetylation may also be mechanistically involved in p53-regulated transcription. Indeed, acetylation at K9 and K14, both of which are regulated by p53, has been associated with chromatin relaxation for transcription (12). Changes in histone acetylation have been observed previously at p53 target genes and there is evidence for differential core histone acetylation at different genes (61). Our own results identify differential effects of p53 upon individual residues within histone H3, a key determinant of chromatin organization. p53 also influences histone H3 modification under normal growth conditions in which p53 is not activated as a transcription factor (observations summarized in Figure 3, see ref. 59 for details). This clearly has important implications and suggests additional roles for p53 in chromatin remodelling beyond UV-induced global relaxation for repair and localized remodelling for transcription.



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Fig. 3. Schematic illustrating the complexity and site-specificity of p53-dependent histone H3 modification. UV, 20 min post-UV-irradiation at 10 J/m2; TSA, TSA-treated for 20 h (see text and ref. 59; figure adapted from ref. 59).

 
It is evident from such observations that the effects of p53 on histone modification are extremely complex perhaps reflecting the central role of p53 in multiple cellular activities that require chromatin remodelling. The remarkable specificity of the effects of p53 on histone modification, with evidence of differential effects of p53 on the same modification of different residues of the same core histone (Figure 3 and ref. 59), indicate that such a complex problem will prove difficult to resolve. This is especially the case because the same modification on different residues can have very different functional consequences (12). There are now 28 different histone residues known to be post-translationally modified (63). Which of these modifications are influenced by p53 and deciphering the consequences of these modifications when they occur is an enormous task but progress in both these areas should greatly facilitate our understanding of the reciprocal relationship between chromatin remodelling and p53 function(s).


    Regulation of S10 H3 phosphorylation by p53—protection against aneuploidy?
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 
In addition to site-specific effects on histone H3 acetylation, p53 also affects levels of phosphorylated S10 of histone H3 (Figure 3 and ref. 59). Phosphorylation of S10 of histone H3 has at least two distinct roles in the cell. At the level of local chromatin remodelling, S10 phosphorylation is important for the transcriptional activation of specific genes including the immediate early genes c-fos and c-jun (6466). On a larger scale of chromatin remodelling, global S10 H3 phosphorylation occurs in G2/M phase of the cell cycle and is required for proper chromosome condensation and segregation at mitosis (710).

The mitotic kinase AIM1/Aurora B appears to be the principal kinase involved in the phosphorylation of S10 H3 for initiation of chromosomal condensation in late G2 (10,67). Significantly, AIM1/Aurora B is over-expressed in many human cancer cell lines and abnormalities in S10 phosphorylation have been shown to cause chromosomal abnormalities and segregation defects resulting in aneuploidy (7,10,68). Loss of p53 also causes abnormalities in S10 H3 phosphorylation (59). Under constitutive growth conditions, we consistently found that total levels of S10P H3 were at least several fold higher in the absence of p53 (59). Moreover, whereas total levels of S10P H3 remained relatively constant in response to various treatments in p53+/+ cells, in the absence of p53 levels of S10P H3 were found to vary enormously in a tight inverse relationship with total levels of acetylated K9 H3 (59). It seems that in the absence of p53, S10P levels are dictated to a large extent by the levels of acetylated K9. Such dependency upon the levels of another modification is potentially very dangerous for the cell as it may not allow appropriate regulation of S10 phosphorylation, which is critical for proper chromosomal condensation for mitosis and the maintenance of a normal ploidy. Abnormal S10P H3 levels were also observed in p53–/– cells following release from nocodazole-induced G2/M arrest and this correlated with impaired cell cycle recovery (59), possibly due to defective chromosomal management.

Abnormalities in S10 phosphorylation in the absence of p53 may contribute to the development of aneuploidy, a critical step in carcinogenesis (69). By regulating S10 H3 phosphorylation p53 may support the fidelity of mitosis and cell ploidy.


    Perspective/future directions
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 
Recent advances suggest that chromatin remodelling plays a crucial role in p53 function and that this extends beyond its role as a transcription factor (Figure 4). The field now awaits further studies to decipher exactly how p53 exerts its effects on chromatin. How, for example, does p53 induce global chromatin relaxation for GGR? This may be mediated, in part, through recruitment of p300 by p53 to chromatin and acetylation of lysine 9 of histone H3 but is this really sufficient, or are other HATs and chromatin modifying complexes involved? We have shown that p53 differentially affects multiple modifications of the same core histone. Further work is now needed to elucidate the functional consequences of this distinct pattern of histone modifications and to determine how p53 achieves its specificity.



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Fig. 4. Schematic summarizing the central role of chromatin remodelling in p53 function as guardian of the genome. In addition to local chromatin remodelling for transcription, p53 can also influence chromatin on a global scale, important for GGR (43) and may also support the fidelity of mitosis and ploidy through global alterations in chromatin structure (ref. 59; see text for further details).

 
Research into chromatin modification has exploded in recent years and while the original correlation of increased histone acetylation with a more relaxed chromatin structure still applies (70) it is also clear that this is something of an oversimplification. A histone code exists with proteins able to distinguish between different modifications through modification-specific binding domains (such as chromo- and bromodomains) (71,72) and through a combinatorial approach even the same modification on different residues (4,12). As the case of methylated K9 and K4 of histone H3 exemplifies, the same modification of different residues of the same histone cannot be presumed equivalent (6). Clearly there is a need to define in detail the pattern of modification at specific genes. For example, how does the pattern of histone modification differ between a gene repressed by p53 and a gene activated by p53? Is the effect of p53 on the pattern of histone modification the same for all genes that are transactivated by the tumour suppressor? Do the effects vary depending upon stress and how do they correlate with the pattern of gene expression, i.e. choice between growth arrest or death? Chromatin immunoprecipitation coupled with engineered mutation of histones at selected sites (4) will prove invaluable in addressing such questions. For example, Thanos and co-workers have used a reconstituted in vitro transcription system with nucleosomal templates assembled with wild-type, mutant and modified histones to define the specific role of particular histone modifications in activation of the IFN-ß gene (4). The relationship between chromatin remodelling and p53 is a very worthwhile topic for investigation and may hold important insights into the multiplicity of p53 functions in mammalian cells.


    Acknowledgments
 
We are indebted to Bert Vogelstein for making available the isogenic clones of HCT116 p53+/+ and p53–/– cells. This work was funded by a Yorkshire Cancer Research project grant (to J.M.).


    References
 Top
 Abstract
 Introduction
 p53 transcriptional regulation:...
 Global chromatin remodelling for...
 p53 and histone...
 Regulation of S10 H3...
 Perspective/future directions
 References
 

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Received April 15, 2004; revised June 2, 2004; accepted June 6, 2004.