Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs

Sanford, Samantha L; Welfer, Griffin A.; Freudenthal, Bret; Opresko, Patricia L.

doi:10.1038/s41467-020-19115-y

Cited by 38 publications

(15 citation statements)

References 71 publications

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“…Another class of molecules that affect telomerase activity include nucleoside analogs such as 6-thio-2’-deoxyguanosine (6dG), didanosine (ddITP), azidothymidine (AZT-TP), and 5-fluro-2’deoxyuridine (5-FdU). These compounds when incorporated at the telomeric ends by telomerase leads to chain termination and uncapping of the telomeric ends ( 94 ). Uncapping by nucleoside analogs prevents binding of the shelterin complex, thereby activating DDR.…”

Section: Telomeres and Telomerase Targeted Cancer Therapiesmentioning

confidence: 99%

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Jebaraj

Stilgenbauer

2021

Front. Oncol.

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Telomeres are nucleprotein structures that cap the chromosomal ends, conferring genomic stability. Alterations in telomere maintenance and function are associated with tumorigenesis. In chronic lymphocytic leukemia (CLL), telomere length is an independent prognostic factor and short telomeres are associated with adverse outcome. Though telomere length associations have been suggested to be only a passive reflection of the cell’s replication history, here, based on published findings, we suggest a more dynamic role of telomere dysfunction in shaping the disease course. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. In addition, cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation thus may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. On the other hand, activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. In summary, multiple components of the telomere system are affected and they play an important role in CLL pathogenesis, progression, and clonal evolution. However, processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered.

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Section: Telomeres and Telomerase Targeted Cancer Therapiesmentioning

confidence: 99%

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Jebaraj

Stilgenbauer

2021

Front. Oncol.

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“…Telomerase can also insert 2-OH-dATP, but this addition impairs telomere lengthening by interfering with telomerase translocation. Even the telomerase repeat addition processivity factor POT1-TPP1 is unable to rescue the 8-oxo-dGTP or 2-OH-dATP inhibition of telomerase extension (Sanford et al, 2020). Consistent with oxidized dNTPs inhibiting telomerase, MTH1 depletion in telomerase expressing cancer cells with short telomeres causes telomere loss and dysfunction, and apoptosis (Fouquerel et al, 2016).…”

Section: Mth1 Function In Removal Of Oxidatively Damaged Dntps At Telomeresmentioning

confidence: 96%

Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress

Rosa

Johnson

Opresko

2021

Front. Cell Dev. Biol.

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Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.

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“…Tenofovir is a nucleoside antiretroviral drug that acts by inhibiting the reverse transcriptase enzyme [118]. Tenofovir also inhibits the activity of human telomerase [119], a crucial enzyme for tumorigenesis and cancer proliferation, whose inhibition represents a promising therapeutic strategy in cancer treatment [120,121]. Sherif et al demonstrated that rats receiving tenofovir at a dose of 50 mg/kg for 24 weeks had diminished colorectal cell proliferation attributed to decreased Bcl-2 and cyclin D1 expression [60].…”

Section: Anti-retroviral Drugsmentioning

confidence: 99%

Overcoming Therapy Resistance in Colon Cancer by Drug Repurposing

Yibirin

Oliveira-Gomes²,

Machaalani

et al. 2022

Cancers

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Colorectal cancer (CRC) is the third most common cancer in the world. Despite improvement in standardized screening methods and the development of promising therapies, the 5-year survival rates are as low as 10% in the metastatic setting. The increasing life expectancy of the general population, higher rates of obesity, poor diet, and comorbidities contribute to the increasing trends in incidence. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC with the advantage of treating underlying comorbidities and decreasing chemotherapy toxicity. This review elaborates on the current data that supports drug repurposing as a feasible option for patients with CRC with a focus on the evidence and mechanism of action promising repurposed candidates that are widely used, including but not limited to anti-malarial, anti-helminthic, anti-inflammatory, anti-hypertensive, anti-hyperlipidemic, and anti-diabetic agents.

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Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs

Cited by 38 publications

References 71 publications

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress

Overcoming Therapy Resistance in Colon Cancer by Drug Repurposing

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