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)

Rev7p has been suggested to play an important role in regulating DNA damage response in yeast, and recently, the human homologue (i.e., MAD2B) has been identified, which shares significant homology to the mitotic checkpoint protein MAD2. In this study, we investigated whether MAD2B played a key role in cellular sensitivity to DNA-damaging anticancer drugs by suppressing its expression using RNA interference in nasopharyngeal carcinoma cells. Using colony formation assay, we found that suppression of MAD2B conferred hypersensitivity to a range of DNA-damaging agents, especially DNA cross-linkers, such as cisplatin, and gamma-irradiation. This effect was associated with reduced frequencies of spontaneous and drug-induced mutations, elevated phosphorylation of histone H2AX, and markedly increased chromosomal aberrations in response to DNA damage. In addition, there was also a significant decrease in cisplatin-induced sister chromatid exchange rate, a marker for homologous recombination-mediated post-replication repair in MAD2B-depleted cells. These results indicate that MAD2B may be a key factor in regulating cellular response to DNA damage in cancer cells. Our findings reveal a novel strategy for cancer therapy, in which cancer cells are sensitized to DNA-damaging anticancer drugs through inactivation of the MAD2B gene.
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PMID:Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents. 1661 61

Here we show that the human BubR1 and MAD2 genes, which encode inhibitors of the anaphase promoting complex (APC/C), are directly activated by the oncogenic transcription factor c-MYC via E-box sequences in their first introns. In colorectal cancer biopsies elevated expression of c-MYC correlated with increased MAD2 levels. Activation of a conditional c-MYC allele delayed progression through mitosis in pro-metaphase in a MAD2- and BubR1-dependent manner. A fraction of the daughter cells derived from extended mitotic events underwent synchronous apoptosis, which was in part mediated by BubR1. Furthermore, c-MYC activation resulted in CIN (chromosomal instability) in the diploid MIN (microsatellite instability) cell line DLD-1 and further enhanced CIN in the aneuploid CIN-line MCF7. Unexpectedly, c-MYC-induced CIN was independent of c-MYC-induced BubR1/MAD2 expression and mitotic delay. Therefore, c-MYC-induced CIN may be caused be alternative pathways. We observed that activation of c-MYC induced DNA double-strand breaks, as evidenced by formation of gamma-H2AX foci, which colocalized with foci of active DNA replication. Furthermore, c-MYC activation resulted in mitotic chromosomes exhibiting DNA damage. Therefore, oncogenic deregulation of c-MYC prevents repair of replication-stress induced DNA lesions in the G(2)-phase. We suggest that the c-MYC-mediated persistence of DNA lesions throughout mitosis leads to chromosomal missegregation and underlies c-MYC-induced CIN. The effects of deregulated c-MYC on progression through mitosis described here may have important implications for the origin of chromosomal instability in many tumor types and the sensitivity towards cancer therapeutic agents targeting DNA or the mitotic spindle.
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PMID:c-MYC delays prometaphase by direct transactivation of MAD2 and BubR1: identification of mechanisms underlying c-MYC-induced DNA damage and chromosomal instability. 1729 7

MAD2 (mitotic arrest deficient 2) is a key regulator of mitosis. Recently, it had been suggested that MAD2-induced mitotic arrest mediates DNA damage response and that upregulation of MAD2 confers sensitivity to DNA-damaging anticancer drug-induced apoptosis. In this study, we report a potential novel role of MAD2 in mediating DNA nucleotide excision repair through physical interactions with two DNA repair proteins, XPD (xeroderma pigmentosum complementation group D) and ERCC1. First, overexpression of MAD2 resulted in decreased nuclear accumulation of XPD, a crucial step in the initiation of DNA repair. Second, immunoprecipitation experiments showed that MAD2 was able to bind to XPD, which led to competitive suppression of binding activity between XPD and XPA, resulting in the prevention of physical interactions between DNA repair proteins. Third, unlike its role in mitosis, the N-terminus domain seemed to be more important in the binding activity between MAD2 and XPD. Fourth, phosphorylation of H2AX, a process that is important for recruitment of DNA repair factors to DNA double-strand breaks, was suppressed in MAD2-overexpressing cells in response to DNA damage. These results suggest a negative role of MAD2 in DNA damage response, which may be accounted for its previously reported role in promoting sensitivity to DNA-damaging agents in cancer cells. However, the interaction between MAD2 and ERCC1 did not show any effect on the binding activity between ERCC1 and XPA in the presence or absence of DNA damage. Our results suggest a novel function of MAD2 by interfering with DNA repair proteins.
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PMID:MAD2 interacts with DNA repair proteins and negatively regulates DNA damage repair. 1859 77