Gene/Protein
Disease
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Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
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Query: UNIPROT:P16104 (
H2AX
)
3,930
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
p53-dependent G(1) and G(2) cell cycle checkpoints are activated in response DNA damage that help to maintain genomic stability. p53 also helps to protect cells from damage that occurs during S phase, for example, when the cells are starved for DNA precursors or irradiated with a low dose of UV. p53 is activated in normal cells starved for pyrimidine nucleotides by treatment with N-(phosphonacetyl)-l-aspartate (PALA). The treated cells progress through a first S phase with kinetics similar to those of untreated cells. However, the DNA of the treated cells begins to become damaged rapidly, within 12 h, as revealed by a comet assay, which detects broken DNA, and by staining for phosphorylated histone
H2AX
, which accumulates at sites of DNA damage. Because the cells survive, the damage must be reversible, suggesting single-strand breaks or gaps as the most likely possibility. The transiently damaged DNA stimulates activation of ATR and CHK1, which in turn catalyze the phosphorylation and accumulation of p53. Although PALA-induced DNA damage occurs only in dividing cells, the p53 that is activated is only competent to transcribe genes such as p21 and
macrophage inhibitory cytokine 1
(whose products regulate G(2) and G(1) or S phase checkpoints, respectively) after the cells have exited the S phase during which damage occurs. We propose that p53 is activated by stimulation of mismatch repair in response to the misincorporation of deoxynucleotides into newly synthesized DNA, long before the lack of pyrimidine nucleoside triphosphates causes the rate of DNA synthesis to slow appreciably.
...
PMID:DNA synthesis from unbalanced nucleotide pools causes limited DNA damage that triggers ATR-CHK1-dependent p53 activation. 1843 39
Since DNA damage is a first incident occurred during a tumour attack, it is rational that
histone H2A.X
phosphorylation on tyrosine 39 (H2A.X
Y39ph
) may act as a tumour-relevant factor. This study was aimed to test the authenticity of the hypothesis. Uveal melanoma MP65 cells were transfected for expression of KRas mutated. H2A.X phosphorylation and ERK1/2 was measured, and transwell experiment was performed to examine the consequents of H2A.X
Y39ph
on MP65 cells developing and migration. Regulatory relationship between H2A.X
Y39ph
and ERK1/2 downstream genes were measured. Moreover, whether JMJD6 and MDM2 are involved in H2A.X phosphorylation was studied. Mutation of Ras activated ERK1/2 signalling and inhibited H2A.X phosphorylation at Y39. Silence of H2A.X
Y39ph
contributed to the regulation of MP65 cells growth, migration and transcription of ERK1/2 downstream genes, including CYR61, IGFBP3, WNT16B, NT5E,
GDF15
and CARD16. The repressed H2A.X phosphorylation through Ras-ERK1/2 signalling might be through MDM2-mediated JMJD6 degradation. Our study suggested that Ras-ERK1/2 signalling inhibited H2A.X phosphorylation at Y39, which led to the uncontrolled developing and migration of uveal melanoma cells. In addition, H2A.X phosphorylation was mediated possibly through JMJD6 which could be degraded by MDM2.
...
PMID:KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39. 3173 61
