Crosstalk between site-specific modifications on p53 and histone H3

Warnock, L J; Adamson, Rachel; Lynch, Cian J.; Milner, Jo

doi:10.1038/sj.onc.1210787

Cited by 13 publications

(35 citation statements)

References 27 publications

(35 reference statements)

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“…This suggests that JMJD2B/hKDM4B is a putative target of p53, because other genes are involved in NER, such as DDB1 and XPC (42). In addition, it has been reported that overexpression of p53 generates a reduction in levels of H3K9me2 in cultured human cells (41). Our results are compatible with these reports, because dKDM4B may also demethylate H3K9me2, suggesting that demethylation of H3K9me3 following UV irradiation requires the activation of the dKDM4B gene through Dmp53.…”

Section: Dynamics Of Histone Modifications Insupporting

confidence: 82%

“…In particular, p53 modulates the transcription of multiple factors involved in DNA repair, apoptosis, and cell cycle arrest (41). In this work, we found that UV irradiation results in an increase in the mRNA and protein levels of the H3K9me3 demethylase dKDM4B.…”

Section: Dynamics Of Histone Modifications Inmentioning

confidence: 49%

“…Genotoxic stress activates p53 (among other factors) to trigger the mechanisms of DNA repair in animal cells (41). In particular, p53 modulates the transcription of multiple factors involved in DNA repair, apoptosis, and cell cycle arrest (41).…”

Section: Dynamics Of Histone Modifications Inmentioning

confidence: 99%

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Drosophila p53 Is Required to Increase the Levels of the dKDM4B Demethylase after UV-induced DNA Damage to Demethylate Histone H3 Lysine 9

Palomera-Sánchez

Bucio‐Mendez

Valadéz-Graham³

et al. 2010

Journal of Biological Chemistry

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Chromatin undergoes a variety of changes in response to UVinduced DNA damage, including histone acetylation. In human and Drosophila cells, this response is affected by mutations in the tumor suppressor p53. In this work, we report that there is a global decrease in trimethylated Lys-9 in histone H3 (H3K9me3) in salivary gland cells in wild type flies in response to UV irradiation. In contrast, flies with mutations in the Dmp53 gene have reduced basal levels of H3K9me3, which are then increased after UV irradiation. The reduction of H3K9me3 in response to DNA damage occurs preferentially in heterochromatin. Our experiments demonstrate that UV irradiation enhances the levels of Lys-9 demethylase (dKDM4B) transcript and protein in wild type flies, but not in Dmp53 mutant flies. Dmp53 binds to a DNA element in the dKdm4B gene as a response to UV irradiation. Furthermore, heterozygous mutants for the dKdm4B gene are more sensitive to UV irradiation; they are deficient in the removal of cyclobutane-pyrimidine dimers, and the decrease of H3K9me3 levels following DNA damage is not observed in dKdm4B mutant flies. We propose that in response to UV irradiation, Dmp53 enhances the expression of the dKDM4B histone demethylase, which demethylates H3K9me3 preferentially in heterochromatin regions. This mechanism appears to be essential for the proper function of the nucleotide excision repair system.In eukaryotic cells, the dynamics of chromatin structure play a central role in all processes involving nuclear DNA, including transcription, replication, recombination, and repair. It has been shown that ATP-dependent complexes that alter the structure and array of nucleosomes, together with complexes containing enzymes that modify different histone residues, are the primary modulators of chromatin structure.The most extensively studied histone modifications include acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation (1, 2). It is possible to correlate the status of the chromatin with the residue that is modified and the type of modification, in a manner that is dependent on the specific histone involved. Some histone modifications are prevalent in heterochromatic regions, and others are preferentially linked to euchromatin. For instance, in the case of DNA transcription and replication, it is generally accepted that relaxed chromatin facilitates the incorporation of factors that recognize elements in the DNA, allowing multisubunit complexes to assemble and achieve these functions. A similar situation may occur during DNA repair, because the DNA repair machinery has to repair DNA in the context of chromatin (3).DNA damage by UV irradiation in eukaryotic cells is repaired via the nucleotide excision repair (NER) 3 mechanism. In vitro reconstituted assays have demonstrated that removal of a lesion requires recognition by XPC-HR23b and subsequent unwinding of the DNA duplex by TFIIH (3, 4). The resulting single strands of DNA are then stabilized by xeroderma pigmentosum A and replication pro...

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Section: Dynamics Of Histone Modifications Insupporting

confidence: 82%

Section: Dynamics Of Histone Modifications Inmentioning

confidence: 49%

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Drosophila p53 Is Required to Increase the Levels of the dKDM4B Demethylase after UV-induced DNA Damage to Demethylate Histone H3 Lysine 9

Palomera-Sánchez

Bucio‐Mendez

Valadéz-Graham³

et al. 2010

Journal of Biological Chemistry

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“…Mutation of Arg at P −2 positions to S183, T211, S215, and S269 might turn off Aurora-B recognition. It is known that phosphorylation of nearby sites (like S6/S9 and S33/S37) are interdependent [83,84], which is equivalent to perturbations near the phosphorylation site.…”

Section: Resultsmentioning

confidence: 99%

Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs

Huang

Liu

et al. 2014

IJMS

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p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated in human cancer, using a bioinformatics approaches, we examined the phosphorylation site and its nearby flanking residues, focusing on the consensus phosphorylation motif pattern, amino-acid correlations within the phosphorylation motifs, the propensity of structural disorder of the phosphorylation motifs, and cancer mutations observed within the phosphorylation motifs. Many p53 phosphorylation sites are targets for several kinases. The phosphorylation sites match 17 consensus sequence motifs out of the 29 classified. In addition to proline, which is common in kinase specificity-determining sites, we found high propensity of acidic residues to be adjacent to phosphorylation sites. Analysis of human cancer mutations in the phosphorylation motifs revealed that motifs with adjacent acidic residues generally have fewer mutations, in contrast to phosphorylation sites near proline residues. p53 phosphorylation motifs are mostly disordered. However, human cancer mutations within phosphorylation motifs tend to decrease the disorder propensity. Our results suggest that combination of acidic residues Asp and Glu with phosphorylation sites provide charge redundancy which may safe guard against loss-of-function mutations, and that the natively disordered nature of p53 phosphorylation motifs may help reduce mutational damage. Our results further suggest that engineering acidic amino acids adjacent to potential phosphorylation sites could be a p53 gene therapy strategy.

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“…It is already established that acetylation at K9 and K14 of histone H3 is associated with the relaxation of chromatin for transcription (22), whereas the acetylation levels at these sites were very low in the SiHa cells (19,23). Although wild-type p53 does not induce acetylation at K9 and K14 of histone H3 (24), it was reported that the presence of p53 likely inhibits K9 deacetylation and facilitates K14 acetylation in response to UV irradiation (23). Therefore, other mechanisms exist by which NDGA induces histone H3 acetylation.…”

Section: Discussionmentioning

confidence: 99%

Nordihydroguaiaretic acid inhibits growth of cervical cancer SiHa cells by up-regulating p21

et al. 2010

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Abstract. Nordihydroguaiaretic acid (NDGA) and its derivatives possess anti-cancer effects on various types of cancer via the induction of apoptosis or cell cycle arrest. This study proved that NDGA inhibited cervical cancer SiHa cell growth and induced cell cycle arrest at the G 1 phase, which may be a consequence of cell cycle kinase inhibitor p21 induction. NDGA promoted acetylation of histone H3 in total and p21 gene-associated chromatin. This effect is gene selective, since NDGA has no impact on the p27 gene. NDGA also inhibited HPV-16 E6 gene transcription, which in turn resulted in the restoration of p53 protein levels. The silencing mediator for retinoid and thyroid hormone receptors (SMRT) is a key component of the HDAC3-HDAC4-N-CoR/SMRT complex. We found that NDGA significantly inhibited the transcription of SMRT, which, together with p53, may aid in the detection of the increase of histone H3 acetylation within the p21 gene. Our results suggest that NDGA induces p21 transcription by selectively elevating histone H3 acetylation associated with p21 gene and p53 protein levels via the inhibition of HPV-16 E6 expression.

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Crosstalk between site-specific modifications on p53 and histone H3

Cited by 13 publications

References 27 publications

Drosophila p53 Is Required to Increase the Levels of the dKDM4B Demethylase after UV-induced DNA Damage to Demethylate Histone H3 Lysine 9

Drosophila p53 Is Required to Increase the Levels of the dKDM4B Demethylase after UV-induced DNA Damage to Demethylate Histone H3 Lysine 9

Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs

Nordihydroguaiaretic acid inhibits growth of cervical cancer SiHa cells by up-regulating p21

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