Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HDAC inhibitors induce histone hyperacetylation by a relative increase of histone acetyltransferase activity. Histone hyperacetylation may affect chromatin structure and susceptibility to DNA-damaging stress, such as IR. We here investigate whether these inhibitors can radiosensitize human gastric MKN45 and colorectal DLD1 adenocarcinoma cells. In both cells, FK228 pretreatment at minimally toxic concentrations clearly augmented IR-induced cell death, DNA fragmentation and caspase-3/-8 activation. In contrast, 5-FU did not clearly augment IR-induced cell death and caspase-3 activation. FK228 increased expression of proapoptotic BH3-only Bim proteins, and gene transfer-mediated overexpression of Bimalpha radiosensitized DLD1 cells. These data suggest that the FK228-mediated increase of Bim expression may at least partially contribute to its augmentation of radiation-induced apoptosis. However, FK228 did not distinctly affect IR-induced phosphorylation of H2AX, which is an initial event followed by DNA damage. FK228 strongly augmented IR-induced growth suppression of MKN45 tumor xenografts. In addition, other HDAC inhibitors, MS275 and CBHA, similarly augmented IR-induced cell death in both cell types. Our results suggest that these HDAC inhibitors may enhance the efficacy of radiation therapy in gastrointestinal cancer cells.
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PMID:Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. 1506 98

Modulation of chromatin is essential to nuclear processes that utilize DNA, such as transcription, replication, and repair. For example, transcription is assisted by histone post-translational modifications, as well as chromatin-remodeling complexes, which alter the structure of chromatin. Furthermore, recent advancements in the fields of DNA repair and chromatin reveal that both histone modifications and chromatin-remodeling complexes are essential for the repair of DNA lesions. In particular, chromatin-modifying complexes, such as the INO80 chromatin-remodeling complex and the Tip60 histone acetyltransferase complex, associate with the DNA damage-induced phosphorylated H2AX, which is often referred to as gamma-H2AX. In S. cerevisiae, the association of INO80 with gamma-H2AX is required for the recruitment of INO80 to sites of DNA double-strand breaks. Additionally, in Drosophila, Tip60 exchanges gamma-H2AX for unmodified H2A in regions of DNA damage. This report reviews recent studies that emphasize the intimate relationship between evolutionarily-conserved chromatin-modifying complexes and histone post-translational modifications in the repair of DNA damage.
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PMID:DNA repair in the context of chromatin. 1575 56

Chromatin reorganization plays an important role in DNA repair, apoptosis, and cell cycle checkpoints. Among proteins involved in chromatin reorganization, TIP60 histone acetyltransferase has been shown to play a role in DNA repair and apoptosis. However, how TIP60 regulates chromatin reorganization in the response of human cells to DNA damage is largely unknown. Here, we show that ionizing irradiation induces TIP60 acetylation of histone H2AX, a variant form of H2A known to be phosphorylated following DNA damage. Furthermore, TIP60 regulates the ubiquitination of H2AX via the ubiquitin-conjugating enzyme UBC13, which is induced by DNA damage. This ubiquitination of H2AX requires its prior acetylation. We also demonstrate that acetylation-dependent ubiquitination by the TIP60-UBC13 complex leads to the release of H2AX from damaged chromatin. We conclude that the sequential acetylation and ubiquitination of H2AX by TIP60-UBC13 promote enhanced histone dynamics, which in turn stimulate a DNA damage response.
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PMID:DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. 1770 92

MORF4-related gene on chromosome 15 (MRG15) is a core component of the NuA4/Tip60 histone acetyltransferase complex that modifies chromatin structure. We here demonstrate that Mrg15 null and heterozygous mouse embryonic fibroblasts exhibit an impaired DNA-damage response post gamma irradiation, when compared to wild-type cells. Defects in DNA-repair and cell growth, and delayed recruitment of repair proteins to sites of damage were observed. Formation of phosphorylated H2AX and 53BP1 foci was delayed in Mrg15 mutant versus wild-type cells following irradiation. These data implicate a novel role for MRG15 in DNA-damage repair in mammalian cells.
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PMID:Mrg15 null and heterozygous mouse embryonic fibroblasts exhibit DNA-repair defects post exposure to gamma ionizing radiation. 1796 56

The role of chromatin-remodeling factors in transcription is well established, but the link between chromatin-remodeling complexes and DNA repair remains unexplored. Human Rvb1 and Rvb2 are highly conserved AAA(+) ATP binding proteins that are part of various chromatin-remodeling complexes, such as Ino80, SNF2-related CBP activator protein (SRCAP), and Tip60/NuA4 complexes, but their molecular function is unclear. The depletion of Rvb1 increases the amount and persistence of phosphorylation on chromatin-associated H2AX after the exposure of cells to UV irradiation or to mitomycin C, cisplatin, camptothecin, or etoposide, without increasing the amount of DNA damage. Tip60 depletion, but not Ino80 or SRCAP depletion, mimics the effect of Rvb1 depletion on H2AX phosphorylation. Rvb1 is required for the histone acetyltransferase (HAT) activity of the Tip60 complex, and histone H4 acetylation is required prior to the dephosphorylation of phospho-H2AX. Thus, Rvb1 is critical for the dephosphorylation of phospho-H2AX due to the role of Rvb1 in maintaining the HAT activity of Tip60/NuA4, implicating the Rvb1-Tip60 complex in the chromatin-remodeling response of cells after DNA damage.
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PMID:Human Rvb1/Tip49 is required for the histone acetyltransferase activity of Tip60/NuA4 and for the downregulation of phosphorylation on H2AX after DNA damage. 1828 60

Certain actin-related proteins (Arps) of budding yeast are localized in the nucleus, and have essential roles as stoichiometric components of histone acetyltransferase (HAT) and chromatin remodeling complexes. On the other hand, identification of vertebrate nuclear Arps and their functional analyses are just beginning. We show that human Arp5 (hArp5) proteins are localized in the nucleus, and that arp5Delta yeast cells are partially complemented by hArp5. Thus, hArp5 is a novel member of the nuclear Arps of vertebrates, which possess evolutionarily conserved functions from yeast to humans. We show here that hArp5 shuttles between the nucleus and the cytoplasm. Furthermore, after the induction of DNA double strand breaks (DSB), cell growth and the accumulation of phosphorylated histone H2AX (gamma-H2AX) are impaired by hArp5 depletion. Association of hArp5 with the hIno80 chromatin remodeling enzyme and decrease of chromatin-bound hIno80 by hArp5-depletion indicate that hArp5 may have a role in the recruitment of the hINO80 complex to chromatin. Overexpression of hArp5 and hIno80 enhanced gamma-H2AX accumulation. These observations suggest that hArp5 is involved in the process of DSB repair through the regulation of the chromatin remodelling machinery.
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PMID:The human actin-related protein hArp5: nucleo-cytoplasmic shuttling and involvement in DNA repair. 1901 34

Matrix metalloproteinase (MMP)-1 promotes ultraviolet (UV)-triggered long-term detrimental effects such as cancer formation and premature skin aging. Although histone modifications may play a crucial role in the transcriptional regulation of MMP-1, the relationship between UV-induced histone modification and MMP-1 expression is not completely understood. Here, we identify regulators of histone acetylation that may link UV-mediated DNA damage and MMP-1 induction by UV in cultured human dermal fibroblasts (HDFs) in vitro. UV irradiation of HDFs induced MMP-1 expression and increased the level of phosphorylation of H2AX (gamma-H2AX), p53 and the acetylation of histone H3 (acetyl-H3). Total histone deacetylase (HDAC) enzymatic activity was decreased by UV irradiation, while histone acetyltransferase (HAT) activity was increased. Suppression of p300 histone acetyltransferase (p300HAT) activity by the p300HAT inhibitor anacardic acid (AA) or by down-regulation of p300 by siRNA prevented UV-induced MMP-1 expression and inhibited UV-enhanced gamma-H2AX, p53 level, and acetyl-H3. Using chromatin immunoprecipitation assays, we observed that gamma-H2AX, p53, acetyl-H3, p300 and c-Jun were consistently recruited by UV to a distinct region (-2067/-1768) adjacent to the p300 binding site (-1858/-1845) in the MMP-1 promoter. In addition, these recruitments of gamma-H2AX, p53, acetyl-H3, p300 and c-Jun to the p300-2 site were significantly abrogated by post-treatment with AA. Furthermore, overexpression of p300 increased the basal and UV-induced MMP-1 promoter activity. Our results suggest that p300HAT plays a critical role in the transcriptional regulation of MMP-1 by UV.
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PMID:The role of p300 histone acetyltransferase in UV-induced histone modifications and MMP-1 gene transcription. 1928 85

Faithful control of cell cycle checkpoint and DNA repair contributes to prevent the cells from chromosomal instability and tumorigenesis. Dnmt1-associated protein 1 (Dmap1), a component of the NuA4 histone acetyltransferase complex, was originally identified as an interacting molecule with DNMT1 which co-localizes with PCNA at DNA replication foci. However, its role in cellular functions remains largely unknown. Here we show that Dmap1 knockdown in mouse embryonic fibroblasts (MEFs) lead to spontaneous double-strand breaks (DSBs), resulting in growth arrest because of p53-dependent cell cycle checkpoint activation. Deletion of both Dmap1 and p53 in MEFs synergized towards enhanced generation of DSBs, chromosomal abnormalities and tumor development in mice. Notably, we found that, on DNA damage, Dmap1 was recruited to the damaged sites to form complexes with gamma-H2AX and replication factors, including Pcna. Depletion of Dmap1 in MEFs abrogated the stable accumulation of Pcna at the DNA damaged sites. Furthermore, the re-introduction of Dmap1 mutants with a reduced capacity to bind Pcna failed to ameliorate the impaired DNA repair in Dmap1-depleted cells. These findings indicate that Dmap1 is required to involve Pcna in DNA repair. Together, Dmap1 plays a crucial role in DNA repair, and is indispensable for the maintenance of chromosomal integrity.
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PMID:Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process. 1984 71

Although recent studies highlight the importance of histone modifications and ATP-dependent chromatin remodelling in DNA double-strand break (DSB) repair, how these mechanisms cooperate has remained largely unexplored. Here, we show that the SWI/SNF chromatin remodelling complex, earlier known to facilitate the phosphorylation of histone H2AX at Ser-139 (S139ph) after DNA damage, binds to gamma-H2AX (the phosphorylated form of H2AX)-containing nucleosomes in S139ph-dependent manner. Unexpectedly, BRG1, the catalytic subunit of SWI/SNF, binds to gamma-H2AX nucleosomes by interacting with acetylated H3, not with S139ph itself, through its bromodomain. Blocking the BRG1 interaction with gamma-H2AX nucleosomes either by deletion or overexpression of the BRG1 bromodomain leads to defect of S139ph and DSB repair. H3 acetylation is required for the binding of BRG1 to gamma-H2AX nucleosomes. S139ph stimulates the H3 acetylation on gamma-H2AX nucleosomes, and the histone acetyltransferase Gcn5 is responsible for this novel crosstalk. The H3 acetylation on gamma-H2AX nucleosomes is induced by DNA damage. These results collectively suggest that SWI/SNF, gamma-H2AX and H3 acetylation cooperatively act in a feedback activation loop to facilitate DSB repair.
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PMID:A cooperative activation loop among SWI/SNF, gamma-H2AX and H3 acetylation for DNA double-strand break repair. 2022 53

Ataxia telangiectasia mutated (ATM) kinase is a central player in cellular response to DNA damage. Phosphorylation of the histone H2AX by ATM is required for the accumulation of repair proteins at the sites of double-strand breaks. Recently, it was reported that the histone acetyltransferase Tat interactive protein-60 (IPP60) is required to acetylate ATM prior to its activation. The RuvB-like proteins TIP48 and TIP49 are known to be necessary for the assembly and functional activity of the TIP60 acetyltransferase complex. In the present communication, we investigated the requirements of IIP48 and IIP49 for ATM activation by monitoring the cell cycle distribution and H2AX phosphorylation after irradiation of IIP48- and IIP49-depleted cells. We found that neither the cell cycle norgammay-H2AX were affected in IIP48- and IIP49-silenced cells, suggesting that the IIP60 chromatin modification complex is not engaged in DNA damage signaling upstream of ATM.
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PMID:Lack of effect of RuvB-like proteins on DNA damage signaling activation. 2035 35


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