AZT as a telomerase inhibitor

Gomez, Daniel E.; Armando, Romina; Alonso, Daniel F.

doi:10.3389/fonc.2012.00113

Cited by 48 publications

(39 citation statements)

References 35 publications

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“…They are first incubated with AZT (0.8 mM) for 2 weeks. Previously published work suggested that 0.8 mM AZT can induce observable telomere shortening54. Then the genome DNAs are collected and subjected to telomere length measurement.…”

Section: Resultsmentioning

confidence: 99%

Assessing Telomere Length Using Surface Enhanced Raman Scattering

Zong

Wang

Chen

et al. 2014

Sci Rep

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Telomere length can provide valuable insight into telomeres and telomerase related diseases, including cancer. Here, we present a brand-new optical telomere length measurement protocol using surface enhanced Raman scattering (SERS). In this protocol, two single strand DNA are used as SERS probes. They are labeled with two different Raman molecules and can specifically hybridize with telomeres and centromere, respectively. First, genome DNA is extracted from cells. Then the telomere and centromere SERS probes are added into the genome DNA. After hybridization with genome DNA, excess SERS probes are removed by magnetic capturing nanoparticles. Finally, the genome DNA with SERS probes attached is dropped onto a SERS substrate and subjected to SERS measurement. Longer telomeres result in more attached telomere probes, thus a stronger SERS signal. Consequently, SERS signal can be used as an indicator of telomere length. Centromere is used as the inner control. By calibrating the SERS intensity of telomere probe with that of the centromere probe, SERS based telomere measurement is realized. This protocol does not require polymerase chain reaction (PCR) or electrophoresis procedures, which greatly simplifies the detection process. We anticipate that this easy-operation and cost-effective protocol is a fine alternative for the assessment of telomere length.

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Section: Resultsmentioning

confidence: 99%

Assessing Telomere Length Using Surface Enhanced Raman Scattering

Zong

Wang

Chen

et al. 2014

Sci Rep

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“…This effect in cells is related to DNA lesions induced directly by NAs incorporated into genomic DNA, or indirectly by targeting telomerase or ROS-induced oxidative damage. [35][36][37][38][39][40][41][42][43][44][45][46] The phosphorylation occurs soon after DNA damage and accumulates around the break site to attract proteins involved in repair and chromatin remodeling. We found that the level of gH2AX is much greater in both cell lines infected with latent HIV-1, than in un-infected cells, when they were exposed to high concentrations of the NRTI-type of NAs that we tested.…”

Section: Discussionmentioning

confidence: 99%

“…We analyzed DDR by exposing cells to high doses of the anti-HIV class of NAs called nucleoside reverse transcriptase inhibitors (NRTIs), choosing AZT (azidothymidine, zivudine) and d4T (stavudine), which are known to incorporate into genomic DNA, affect telomerase and to induce oxidative stress. 36,[38][39][40][41][42][43][44][45][46] The effects of high doses of NRTIs on DNA damage response in latent cells were analyzed by assessing the level of gamma-H2AX (gH2AX), which is a biomarker of DSBs. The gH2AX protein is a histone H2A variant, H2AX, phosphorylated on serine 139 in response to DSBs.…”

Section: Ddr In Latently Infected Cells Responds Less Efficiently To mentioning

confidence: 99%

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

et al. 2017

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Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells. These results indicate a DDR defect even though the virus is latent. DDR-inducing agents, specifically high doses of nucleoside RT inhibitors (NRTIs), caused greater increases in gamma-H2AX levels in latently infected cells. Additionally, latently infected cells are more susceptible to long-term exposure to G-quadruplex stabilizing agents, and this effect is enhanced when the agent is combined with an inhibitor targeting DNA-PK, which is crucial for DSB repair and telomere maintenance. Moreover, exposing these cells to the cancer drug etoposide resulted in formation of DSBs at a higher rate than in un-infected cells. Similar effects of etoposide were also observed in population of primary memory T cells infected with latent HIV-1. Sensitivity to these agents highlights a unique vulnerability of latently infected cells, a new feature that could potentially be used in developing therapies to eliminate HIV-1 reservoirs.

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“…The ultimate result of all these events is cellular genetic instability and DNA damage [11,23]. AZT affects also the growth of cancer cells by inducing telomere shortening [16,25], through inhibition of telomerase reverse transcriptase activity [15,20] and causing cell cycle arrest. The global result is a remarkable antiproliferative effect, leading in some instances to senescence [10,19].…”

mentioning

confidence: 99%