Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to develop an in vitro human cytomegalovirus (HCMV) latency model system, the growth characteristics of HCMV in a human thyroid papillary carcinoma cell line (TPC-1) were examined. When TPC-1 cultures preheated at 40.5 degrees for 48 hr were infected with HCMV and incubated at a supraoptimal temperature (40.5 degrees), the cultures could be maintained for at least 65 days without detection of infectious virus. In contrast, when the infected cultures were incubated at 37 degrees, HCMV persistently infected cultures were established. HCMV was reactivated from the latently infected cultures by decreasing the incubation temperature from 40.5 to 37 degrees, and the cultures subsequently entered into virus persistent infection. Although HCMV-specific polypeptides which comigrate with the immediate early virus polypeptides and nuclear antigens were continuously detectable in the majority (more than 95%) of the cells during the latent period, a detectable level of virus-specified DNA polymerase (one of the early virus proteins) was not induced, suggesting that the blockage of HCMV replication in the latently infected cultures occurs at the early stages of the HCMV replication cycle. Infectious center assay revealed that 0.002 to 0.2% of the cells contain an HCMV genome that can be activated during the latent period. The latently infected cells were susceptible to superinfection with homologous and heterologous strains of HCMV. In persistently infected cultures approximately 38% of the cells were lysed by reaction with HCMV immune serum and complement, whereas complement-mediated immune cytolysis could not be detected in the latently infected cultures. The data presented suggest that a temperature-sensitive cellular function(s) that controls the expression of the HCMV early functions plays an important role in maintenance of the HCMV genome in the latent state and reactivation of HCMV by decreasing the incubation temperature.
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PMID:Establishment and biological characterization of an in vitro human cytomegalovirus latency model. 282 70

Indomethacin and tetracaine, inhibitors of prostaglandin synthesis, inhibited production of infectious human cytomegalovirus (HCMV) in a human thyroid papillary carcinoma cell line (TPC-1) by 99.9% when added to cultures at the concentration of 2 x 10(-4) M during the first 24 hr after infection. Although immediate early virus proteins were synthesized at similar molar ratios in mock- and compound-treated cultures, induction of HCMV-specific DNA polymerase (one of the early virus proteins) was inhibited by treatment with these compounds, suggesting that the early stages of the virus growth cycle are most likely to be under the control of indomethacin or tetracaine action. We have previously developed an in vitro HCMV latency model system in TPC-1 cultures. This system was used to study the effect of these compounds on reactivation of the latent virus. When TPC-1 cultures preheated for 48 hr at 40.5 degrees were infected with HCMV and incubated at 40.5 degrees, the cultures could be maintained for 30 days without detection of infectious virus. The latent HCMV was reactivated within 10 days by reducing the incubation temperature from 40.5 to 37 degrees. However, when the latently infected cultures were treated with indomethacin or tetracaine immediately after being shifted to 37 degrees, reactivation of the latent virus was not observed.
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PMID:Inhibitors of prostaglandin synthesis inhibit growth of human cytomegalovirus and reactivation of latent virus in a productively and latently infected human cell line. 283 56

Human chromosomal fragile sites are specific genomic regions which exhibit gaps or breaks on metaphase chromosomes following conditions of partial replication stress. Fragile sites often coincide with genes that are frequently rearranged or deleted in human cancers, with over half of cancer-specific translocations containing breakpoints within fragile sites. But until recently, little direct evidence existed linking fragile site breakage to the formation of cancer-causing chromosomal aberrations. Studies have revealed that DNA breakage at fragile sites can induce formation of RET/PTC rearrangements, and deletions within the FHIT gene, resembling those observed in human tumors. These findings demonstrate the important role of fragile sites in cancer development, suggesting that a better understanding of the molecular basis of fragile site instability is crucial to insights in carcinogenesis. It is hypothesized that under conditions of replication stress, stable secondary structures form at fragile sites and stall replication fork progress, ultimately resulting in DNA breaks. A recent study examining an FRA16B fragment confirmed the formation of secondary structure and DNA polymerase stalling within this sequence in vitro, as well as reduced replication efficiency and increased instability in human cells. Polymerase stalling during synthesis of FRA16D has also been demonstrated. The ATR DNA damage checkpoint pathway plays a critical role in maintaining stability at fragile sites. Recent findings have confirmed binding of the ATR protein to three regions of FRA3B under conditions of mild replication stress. This review will discuss recent advances made in understanding the role and mechanism of fragile sites in cancer development.
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PMID:DNA instability at chromosomal fragile sites in cancer. 2128 10