To die or not to die: a HAT trick

ArticleinMolecular Cell 24(6):807-8 · January 2007with5 Reads
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.
    • "By other words, ligand binding results in a repositioning of H12 in the LBD thus enabling the recruitment of SRC coactivators. SRCs interacting with NRs via NR-boxes facilitate the transcription via histone acetylase (HAT) activity intrinsic to SRC (Spencer et al. 1997; Torchia et al. 1997; Utley et al. 1998; Sterner and Berger 2000; Sachs and Shi 2000; Sachs et al. 2001; Black et al. 2006; Pugh 2006; Tyteca et al. 2006 ). In addition, the activation domain 1 (AD1) of SRCs binds to the C-terminal SRC interaction domain (SID) of p300 as well as its homolog, the cAMP response element-binding (CREB) protein (CBP) (Li and Chen 1998; Sheppard et al. 2001; Dutertre and Smith 2003; Ding et al. 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: Classical non-peptide hormones, such as steroids, retinoids, thyroid hormones, vitamin D3 and their derivatives including prostaglandins, benzoates, oxysterols, and bile acids, are collectively designated as small lipophilic ligands, acting via binding to the nuclear receptors (NRs). The NRs form a large superfamily of transcription factors that participate virtually in every key biological process. They control various aspects of animal development, fertility, gametogenesis, and numerous metabolic pathways, and can be misregulated in many types of cancers. Their enormous functional plasticity, as transcription factors, relates in part to NR-mediated interactions with plethora of coregulatory proteins upon ligand binding to their ligand binding domains (LBD), or following covalent modification. Here, we review some general views of a specific group of NR coregulators, so-called nuclear receptor coactivators (NRCs) or steroid receptor coactivators (SRCs) and highlight some of their unique functions/roles, which are less extensively mentioned and discussed in other reviews. We also try to pinpoint few neglected moments in the cooperative action of SRCs, which may also indicate their variable roles in the hormone-independent signaling pathways.
    Full-text · Article · Jul 2016
    • "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). "
    [Show abstract] [Hide abstract] 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.
    Article · Dec 2015
    • "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 . "
    [Show abstract] [Hide abstract] 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.
    Article · May 2013
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