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

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

Histone acetylation induces chromatin opening by perturbing higher-order chromatin compaction and folding, suggesting that histone acetylation and deacetylation dynamics are central to chromosome condensation or decondensation. The condensation of chromosomes during mitosis is an essential prerequisite for successful chromosome segregation. In this study, we depleted three representative histone acetyltransferases (HATs; p300, CBP, and P/CAF) using shRNAs to explore their role in regulating mitotic progression and chromosome segregation. We showed that HAT depletion severely interfered with the normal timing of mitotic progression, and it reduced condensin subunit levels. The predominant response to HAT depletion, in both human primary and cancer cells, was a mitotic catastrophe following aberrant mitotic arrest. Alternatively, adaptation to HAT depletion, particularly in cancer cells, led to multinucleation and aneuploidy. Interestingly, mitotic catastrophe induced by HAT depletion appeared to be coupled to the signaling process of H2AX phosphorylation and foci formation, independently of DNA double-strand breaks and DNA damage. Taken together, our results provide novel molecular evidence that HAT proteins maintain mitotic chromatin assembly and integrity as a cellular determinant of mitotic cell death.
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PMID:Mitotic catastrophe is the predominant response to histone acetyltransferase depletion. 1909 91

We previously showed that in quiescent cells, p300/CBP (CREB-binding protein)family coactivators repress c-myc and prevent premature induction of DNA synthesis. p300/CBP-depleted cells exit G(1) early and continue to accumulate in S phase but do not progress into G(2)/M, and eventually they die of apoptosis. Here, we show that the S-phase arrest in these cells is because of an intra-S-phase block. The inappropriate DNA synthesis that occurs as a result of forced expression of c-myc leads to the activation of the DNA damage response as evidenced by the phosphorylation of several checkpoint related proteins and the formation of foci containing gamma-H2AX. The activation of checkpoint response is related to the induction of c-myc, as the phosphorylation of checkpoint proteins can be reversed when cells are treated with a c-Myc inhibitor or when Myc synthesis is blocked by short hairpin RNA. Using the DNA fiber assay, we show that in p300-depleted cells initiation of replication occurs from multiple replication origins. Chromatin loading of the Cdc45 protein also indicates increased origin activity in p300 knockdown cells. Immunofluorescence experiments indicate that c-Myc colocalizes with replication foci, consistent with the recently reported direct role of c-Myc in the initiation of DNA synthesis. Thus, the inappropriate S-phase entry of p300 down-regulated cells is likely to be because of c-Myc-induced deregulated replication origin activity, which results in replicative stress, activation of a DNA damage response, and S-phase arrest. Our results point to an important role for p300 in maintaining genomic integrity by negatively regulating c-myc.
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PMID:c-Myc-induced aberrant DNA synthesis and activation of DNA damage response in p300 knockdown cells. 1933 36

Phosphorylation of H2AX functions to recruit DNA repair complexes to sites of DNA damage. Here, we report that H2AX is constitutively acetylated on lysine 36 (H2AXK36Ac) by the CBP/p300 acetyltransferases. H2AXK36Ac is required for cells to survive exposure to ionizing radiation; however, H2AXK36Ac levels are not increased by DNA damage. Further, acetylation of H2AX did not affect phosphorylation of H2AX or the formation of DNA damage foci. Finally, cells with a double mutation in both the H2AX acetylation and phosphorylation sites were more radiosensitive than cells containing individual mutations. H2AXK36Ac is therefore a novel, constitutive histone modification located within the histone core region which regulates radiation sensitivity independently of H2AX phosphorylation.
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PMID:Acetylation of H2AX on lysine 36 plays a key role in the DNA double-strand break repair pathway. 2048 83

The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network and serves as an H2AX phosphatase. The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast showed that EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo, requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact-independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1-binding site at -953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II, and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell-cycle control via transcriptional complex formation at the cyclin D1 promoter.
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PMID:EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1. 2363 26

Here we provide evidence that RBBP4 modulates temozolomide (TMZ) sensitivity through coordinate regulation of two key DNA repair genes critical for recovery from TMZ-induced DNA damage: methylguanine-DNA-methyltransferase (MGMT) and RAD51. Disruption of RBBP4 enhanced TMZ sensitivity, induced synthetic lethality to PARP inhibition, and increased DNA damage signaling in response to TMZ. Moreover, RBBP4 silencing enhanced TMZ-induced H2AX phosphorylation and apoptosis in GBM cells. Intriguingly, RBBP4 knockdown suppressed the expression of MGMT, RAD51, and other genes in association with decreased promoter H3K9 acetylation (H3K9Ac) and increased H3K9 tri-methylation (H3K9me3). Consistent with these data, RBBP4 interacts with CBP/p300 to form a chromatin-modifying complex that binds within the promoter of MGMT, RAD51, and perhaps other genes. Globally, RBBP4 positively and negatively regulates genes involved in critical cellular functions including tumorigenesis. The RBBP4/CBP/p300 complex may provide an interesting target for developing therapy-sensitizing strategies for GBM and other tumors.
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PMID:Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins. 2697 1