Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study describes a correlation between cellular DNA repair capacity and the frequency of mutagen-induced in vitro chromosomal breaks in selected lymphoblastoid cell lines. Two assays, host cell reactivation (HCR) assay for measuring cellular DNA repair capacity and in vitro mutagen sensitivity assay, have recently been shown to be useful biomarkers for such susceptibility. Increased in vitro mutagen sensitivity, measured by the number of induced chromatid breaks, has been postulated to reflect decreased capacity of DNA repair, as measured by the HCR assay. However, these two assays have not been examined in parallel to test this hypothesis. In this study, we performed both assays in 16 established lymphoblastoid cell lines derived from patients with xeroderma pigmentosum (n = 3), ataxia telangiectasia (n = 2), head and neck cancer (n = 3), and melanoma (n = 2), and from normal human subjects (n = 6) using UV light, 4-nitroquinoline-1-oxide (4-NQO; an UV-mimetic agent), and gamma-irradiation as the test agents. The measurements from the HCR assay correlated significantly with the frequency of chromatid breaks induced by either UV irradiation (r = -0.69; P < 0.01) or 4-NQO (r = -0.70; P < 0.01). Although published data suggest that damage induced by UV and 4-NQO may be repaired by different pathways, the two agents induced similar frequencies of chromatid breaks (r = 0.68; P < 0.01) in the tested cell lines. Our results also indicated that the HCR assay is not suitable to test agents that cause DNA strand breaks, such as gamma-irradiation, whereas the mutagen sensitivity assay is. Although reduced cellular DNA repair capacity correlated with increased frequency of mutagen-induced chromatid breaks in these cell lines, these two assays have different sensitivities in measuring the repair of damage induced by different carcinogens; therefore, the use of both assays is recommended for future molecular epidemiological studies of cancer susceptibility.
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PMID:DNA repair capacity correlates with mutagen sensitivity in lymphoblastoid cell lines. 883 20

The nucleolus is the site of ribosomal gene transcription, processing of rRNA transcripts and maturation of preribosomal particles. Recent studies have shown that nucleoli are also involved in processes as diverse as aging, proliferation control, stress response and mitotic regulation. The proliferation-dependent nucleolar antigen pKi-67 is a sensitive marker of both proliferative activity and nucleolar integrity. We show that staining for the nucleolar-associated antigen pKi-67 is lost from nucleoli during growth arrest following UV irradiation. Surprisingly, before cells enter growth arrest, Ki-67 staining translocates from nucleolar to nucleoplasmic sites within 4-6 h of irradiation. Ki-67 redistribution is accompanied by segregation of nucleolar components. The timing of p53 response correlates well with pKi-67 translocation, growth arrest and restoration of proliferation. However, nucleolar segregation and pKi-67 translocation occur in the absence of functional p53 and other components of damage response pathways (DNA-PK, CSA, CSB, XPA, XPC, ATM ATR, p38(MAPK) and MEK1). Neither gamma-irradiation nor H(2)O(2) treatment causes pKi-67 translocation or loss of nucleolar integrity. In marked contrast, treatment of cells with UV-mimetic 4-NQO does induce nucleolar disruption and relocalisation of pKi-67, suggesting that bulky adduct formation in rDNA rather than strand breaks is sufficient to cause nucleolar segregation. Our data reveal a previously unrecognized cellular response to genotoxic stress and may reveal novel pathways leading to growth arrest.
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PMID:A p53-independent pathway regulates nucleolar segregation and antigen translocation in response to DNA damage induced by UV irradiation. 1472 May 17