Acetylation of the p53 DNA-Binding Domain Regulates Apoptosis Induction

Sykes, Stephen M.; Mellert, Hestia; Holbert, Marc A.; Li, Keqin; Marmorstein, Ronen; Lane, William S.; McMahon, Steven B.

doi:10.1016/j.molcel.2006.11.026

Cited by 663 publications

(777 citation statements)

References 48 publications

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“…During this period, p53 may undergo a cascade of post-translational modifications including N-and C-terminal phosphorylations, C-terminal acetylation, sumoylation, methylation, ubiquitination and neddylation (Appella and Anderson, 2001;Brooks and Gu, 2003;Sykes et al, 2006). In particular, serines 15 and 37 act as substrates for DNA-PK and ATM following genotoxic stress (Vousden, 2002).…”

Section: Resultsmentioning

confidence: 99%

Crosstalk between site-specific modifications on p53 and histone H3

et al. 2007

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Previously, we have observed a link between p53 expression and histone H3 post-translational modifications. Here, we ask if specific post-translational modifications of p53 impact upon histone H3 modifications in a selective manner. We have also screened for internal co-operative effects within the repertoire of p53 modifications. Exogenous p53 constructs were expressed in HCT116 p53 À/À cells. Four mutant p53 constructs were used, with single 'phosphorylation' mutations at serines 15 and 37 (S15A, S15D, S37A and S37D) and compared with exogenously expressed wild-type p53. The results showed that the replacement of serine 15 with either alanine (S15A) or aspartic acid (S15D) induced phosphorylation at S33P, S37P and S46P. In contrast, phosphorylation mutants p53(S37A) and p53(S37D) were not phosphorylated on S33. S46 phosphorylation appeared specifically enhanced by p53(S37D) relative to p53(S37A). Distal induction of S392 phosphorylation was observed for each of the p53 N-terminal phosphorylation mutants. Analysis of endogenous histone H3 (from the transfected cells) revealed loss of di-methylated K9 following expression of wild type and mutant p53 constructs. Expression of p53 (S15A), (S15D) and (S37A) selectively induced acetylation at K9 and K14. In contrast, wt p53 and p53(S37D) had no effect upon K9 or K14 acetylation. K18 acetylation status was unaffected throughout.

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Section: Resultsmentioning

confidence: 99%

Crosstalk between site-specific modifications on p53 and histone H3

et al. 2007

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“…According to the charge neutralization model (Grunstein, 1997), acetylation of lysine residues would neutralize their positive charge and thus decrease the affinity of basic histones for the negatively charged DNA. This same mechanism could extend to an interaction between the basic tails of GST-pull down Sykes et al, 2006) Asterisks indicate the proteins that are also found in Drosophila MOF-containing complexes.…”

Section: H4k16ac In Chromatin Organizationmentioning

confidence: 91%

Males absent on the first (MOF): from flies to humans

2007

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Histone modifications such as acetylation, methylation and phosphorylation have been implicated in fundamental cellular processes such as epigenetic regulation of gene expression, organization of chromatin structure, chromosome segregation, DNA replication and DNA repair. Males absent on the first (MOF) is responsible for acetylating histone H4 at lysine 16 (H4K16) and is a key component of the MSL complex required for dosage compensation in Drosophila. The human ortholog of MOF (hMOF) has the same substrate specificity and recent purification of the human and Drosophila MOF complexes showed that these complexes were also highly conserved through evolution. Several studies have shown that loss of hMOF in mammalian cells leads to a number of different phenotypes; a G 2 /M cell cycle arrest, nuclear morphological defects, spontaneous chromosomal aberrations, reduced transcription of certain genes and an impaired DNA repair response upon ionizing irradiation. Moreover, hMOF is involved in ATM activation in response to DNA damage and acetylation of p53 by hMOF influences the cell's decision to undergo apoptosis instead of a cell cycle arrest. These data, highlighting hMOF as an important component of many cellular processes, as well as links between hMOF and cancer will be discussed.

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“…It is now known that MYST proteins have important roles in various biological processes (Ceol and Horvitz, 2004;Kusch et al, 2004;Dou et al, 2005;Smith et al, 2005;Mendjan et al, 2006;Sykes et al, 2006;Tang et al, 2006). These enzymes have been the subjects of several excellent reviews Squatrito et al, 2006;Avvakumov and Coˆte´, 2007;Lafon et al, 2007;Rea et al, 2007;Thomas and Voss, 2007).…”

Section: Identification Of Moz Morf and Other Mystic Hatsmentioning

confidence: 99%

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

2007

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Genes of the human monocytic leukemia zinc-finger protein MOZ (HUGO symbol, MYST3) and its paralog MORF (MYST4) are rearranged in chromosome translocations associated with acute myeloid leukemia and/or benign uterine leiomyomata. Both proteins have intrinsic histone acetyltransferase activity and are components of quartet complexes with noncatalytic subunits containing the bromodomain, plant homeodomain-linked (PHD) finger and proline-tryptophan-tryptophan-proline (PWWP)-containing domain, three types of structural modules characteristic of chromatin regulators. Although leukemia-derived fusion proteins such as MOZ-TIF2 promote self-renewal of leukemic stem cells, recent studies indicate that murine MOZ and MORF are important for proper development of hematopoietic and neurogenic progenitors, respectively, thereby highlighting the importance of epigenetic integrity in safeguarding stem cell identity.

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Acetylation of the p53 DNA-Binding Domain Regulates Apoptosis Induction

Cited by 663 publications

References 48 publications

Crosstalk between site-specific modifications on p53 and histone H3

Crosstalk between site-specific modifications on p53 and histone H3

Males absent on the first (MOF): from flies to humans

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

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