To die or not to die: a HAT trick

LBME, CNRS and Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse, France.
Molecular Cell (Impact Factor: 14.02). 01/2007; 24(6):807-8. DOI: 10.1016/j.molcel.2006.12.005
Source: PubMed


In this issue of Molecular Cell, two manuscripts (Sykes et al., 2006) propose that the decision to undergo apoptosis upon DNA damage is mediated through acetylation of p53 within its DNA-binding domain by MYST histone acetyltransferases.

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    • "It first participates in DNA damage signalling through acetylation of ATM, a kinase central to the response to Double Strand Breaks (Sun et al., 2005). Moreover, it is an essential cofactor of the p53 tumour suppressor (Berns et al., 2004; Legube et al., 2004), facilitating p53 transcriptional activity but also, through direct acetylation of p53, its targeting to specific promoters (Sykes et al., 2006; Tang et al., 2006; Tyteca et al., 2006). Accordingly, Tip60 is underexpressed in a wide variety of human cancers (Gorrini et al., 2007; Mattera et al., 2009). "
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    ABSTRACT: Pericentric heterochromatin is a highly compacted structure required for accurate chromosome segregation in mitosis. In mammals, it relies on methylation of histone H3K9 by Suv39H enzymes, which provides a docking site for HP1 proteins, therefore mediating heterochromatin compaction. Here, we show that, when this normal compaction pathway is defective, the histone acetyltransferase Tip60 is recruited to pericentric heterochromatin where it mediates acetylation of histone H4K12. Furthermore, in such context, depletion of Tip60 leads to derepression of satellite transcription, to decompaction of pericentric heterochromatin and to defects in chromosome segregation in mitosis. Finally, we show that depletion of BRD2, a double bromodomain containing protein which binds H4K12ac, phenocopies the Tip60 depletion with respect to heterochromatin decompaction and defects in chromosome segregation. Taken together, in this manuscript, we have identified a new compaction pathway of mammalian pericentric heterochromatin relying on Tip60 and which may be dependent on BRD2 recruitment by H4K12 acetylation. We propose that the underexpression in Tip60 expression observed in many human tumours can promote genetic instability through defective pericentric heterochromatin.
    Preview · Article · Dec 2015 · Molecular biology of the cell
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    • "In this study, we found KAT8 reduction significantly induced p53 expression. Previous reports demonstrate that p53 can be acetylated at K120 by hMOF and TIP60 [23] [24] in response to genotoxic stress, leading an inhibition of p53 protein degradation and subsequent p53 induction. Given that KAT8 is a histone acetyltransferase , p53 induction is unlikely due to a direct inhibition of acetylation by KAT8 inhibition . "
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    ABSTRACT: Histone acetyltransferases (HATs) regulate many critical cancer events, including transcriptional regulation of oncogene and tumor suppressors, chromatin structure and DNA damage response. Abnormal expression of HATs has been reported in a number of cancers. However, cellular functions of HATs in cancer and molecular mechanisms remain largely unclear. Here, we performed a lentiviral vector-mediated RNAi screen to systematically address the function of HATs in lung cancer cell growth and viability. We identified 8 HATs genes involved in A549 cell viability. Further experiments showed that KAT8 regulates G2/M cell cycle arrest through AKT/ERK-cyclin D1 signaling. Moreover, KAT8 inhibition led to p53 induction and subsequently reduced bcl-2 expression. Our results demonstrate an important role of KAT8 in cancer and suggest that KAT8 could be a novel cancer therapeutic target.
    Preview · Article · May 2013 · International journal of clinical and experimental pathology
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    • "p300 and its homolog CBP, play an important role in the execution of multiple biological programs, such as differentiation, senescence and apoptosis [16], [17]. Most, -if not all- of the activities attributed to these proteins take place in the nucleus, via regulation of transcription and promotion of acetylation of many factors, including histones. "
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    ABSTRACT: Several human diseases including neurodegenerative disorders and cancer are associated with abnormal accumulation and aggregation of misfolded proteins. Proteins with high tendency to aggregate include the p53 gene product, TAU and alpha synuclein. The potential toxicity of aberrantly folded proteins is limited via their transport into intracellular sub-compartments, the aggresomes, where misfolded proteins are stored or cleared via autophagy. We have identified a region of the acetyltransferase p300 that is highly disordered and displays similarities with prion-like domains. We show that this region is encoded as an alternative spliced variant independently of the acetyltransferase domain, and provides an interaction interface for various misfolded proteins, promoting their aggregation. p300 enhances aggregation of TAU and of p53 and is a component of cellular aggregates in both tissue culture cells and in alpha-synuclein positive Lewy bodies of patients affected by Parkinson disease. Down-regulation of p300 impairs aggresome formation and enhances cytotoxicity induced by misfolded protein stress. These data unravel a novel activity of p300, offer new insights into the function of disordered domains and implicate p300 in pathological aggregation that occurs in neurodegeneration and cancer.
    Full-text · Article · Nov 2012 · PLoS ONE
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