Telomeres are partly shielded from ultraviolet-induced damage and proficient for nucleotide excision repair of photoproducts

Parikh, Dhvani; Fouquerel, Elise; Murphy, Connor T.; Wang, Hong; Opresko, Patricia L.

doi:10.1038/ncomms9214

Cited by 32 publications

(54 citation statements)

References 61 publications

(97 reference statements)

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“…Measurement of telomere length in HeLa VST and HeLa LT was performed as described in 63,64 with slight modification. Briefly, 3 μg of genomic DNA were digested with a cocktail of 4 restriction enzymes (RsaI, AluI, HindIII, MnlI) for 16 h at 37°C and resolve on 0.8% agarose gel for 16 h 30 min (HeLa VST) or 24 h (HeLa LT).…”

Section: Methodsmentioning

confidence: 99%

Oxidative guanine base damage regulates human telomerase activity

Fouquerel

Lormand

Bose

et al. 2016

Nat Struct Mol Biol

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Changes in telomere length are associated with degenerative diseases and cancer. Oxidative stress and DNA damage have been linked to both positive and negative alterations in telomere length and integrity. Here we examined how the common oxidative lesion 8-oxo-7,8-dihydro-2′-deoxyguanine (8-oxoG) regulates telomere elongation by telomerase. When present in the deoxynucleoside triphosphate pool as 8-oxodGTP, telomerase utilization of the oxidized nucleotide during telomere extension is mutagenic and terminates further elongation. Depletion of the enzyme that removes oxidized dNTPs, MTH1, increases telomere dysfunction and cell death in telomerase positive cancer cells harboring shortened telomeres. In contrast, a pre-existing 8-oxoG within the telomeric DNA sequence promotes telomerase activity by destabilizing G-quadruplex structure in the DNA. We show that the mechanism by which 8-oxoG arises in the telomere, either by insertion of oxidized nucleotides or by direct reaction with free radicals, dictates whether telomerase is inhibited or stimulated and thereby, mediates the biological outcome.

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Section: Methodsmentioning

confidence: 99%

Oxidative guanine base damage regulates human telomerase activity

Fouquerel

Lormand

Bose

et al. 2016

Nat Struct Mol Biol

Self Cite

151

168

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“…The UV sensitivity assay was carried out as previous study with amendment [40]. On the one hand, the OVCAR3 cells were irradiated with UV (254 nm, 0, 5 or 10 J/m 2 ) or not in 96-well plates and incubated in fresh media.…”

Section: Methodsmentioning

confidence: 99%

Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway

Liu

Mei

Tian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Rap1 interacting factor 1 (RIF1) was deemed to be involved in replication timing regulation and DNA damage response. However, little is known about the role of RIF1 in malignancies. Thus, this study aimed to investigate whether the expression of RIF1 is relevant to the response of epithelial ovarian cancer (EOC) patients to cisplatin chemotherapy and its underlying mechanism. Methods: Immunohistochemistry was used for detecting the expression of RIF1 in 72 human ovarian cancer tissues followed by association analysis of RIF1 expression with patients’ responses to platinum-based chemotherapy. The survival analysis of ovarian patients based on platinum chemotherapy was analyzed using online databases. RNA interference of RIF1 was carried out in OVCAR3 and A2780 cell lines, to determine the effect of lacking RIF1 expression on cellular responses to cisplatin by using MTS assay. The nucleotide excision repair (NER) capacity of these cells was assessed by using host-cell reactivation and UV sensitivity assay. Western Blot analysis was carried out to determine the effect of RIF1 on the proteins of NER and apoptosis signaling pathway by using RIF1 knockdown cells. BALB/c nude mice model was used for detection of response to cisplatin in vivo. Results: RIF1 expression was significantly associated with the response of ovarian patients to platinum-based chemotherapy (P< 0.01). In cohorts from online databases, high expression of RIF1 was associated with higher mortality of EOC patients based on platinum chemotherapy (P < 0.01). RIF1 knockdown increased sensitivity to cisplatin in EOC in vitro and in vivo. Deletion of RIF1 impaired the NER activity by inhibiting the NER proteins in ovarian cancer cells. Besides, knockdown of RIF1 enhanced cisplatin-induced apoptosis. Conclusions: RIF1 plays an important role in regulating the expression of NER proteins, which in turn contributes to cellular response to cisplatin and EOC patients’ response to platinum-based chemotherapy. RIF1 knockdown also promotes cisplatin-induced apoptosis. RIF1 may serve as a novel biomarker for predicting platinum-based chemosensitivity and the prognosis of EOC patients.

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“…Human telomeres, for example, are less susceptible to UV induced photo-adducts than bulk chromosomal DNA (Parikh et al, 2015). Further, the shelterin components POT1, TRF1, and TRF2 physically interact with and stimulate factors necessary for repair of oxidative and UV damage (Miller et al, 2012;Parikh et al, 2015). In Arabidopsis, both AtTEN1 protein and mRNA are rapidly responsive to temperature and perhaps other environmental stimuli.…”

Section: Ten1 As a Guardian For Telomere Integritymentioning

confidence: 99%

“…Studies in human cells support the conclusion that telomere protein complexes evolved multiple interconnected strategies to stabilize and actively restore the integrity of chromosome ends in response to environmental assault. Human telomeres, for example, are less susceptible to UV induced photo-adducts than bulk chromosomal DNA (Parikh et al, 2015). Further, the shelterin components POT1, TRF1, and TRF2 physically interact with and stimulate factors necessary for repair of oxidative and UV damage (Miller et al, 2012;Parikh et al, 2015).…”

Section: Ten1 As a Guardian For Telomere Integritymentioning

confidence: 99%

Dynamic Interactions of Arabidopsis TEN1: Stabilizing Telomeres in Response to Heat Stress

et al. 2016

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Telomeres are the essential nucleoprotein structures that provide a physical cap for the ends of linear chromosomes. The highly conserved CST (CTC1/STN1/TEN1) protein complex facilitates telomeric DNA replication and promotes telomere stability. Here we report three unexpected properties of Arabidopsis thaliana TEN1 that indicate it possesses functions distinct from other previously characterized telomere proteins. First, we show that telomeres in ten1 mutants are highly sensitive to thermal stress. Heat shock causes abrupt and dramatic loss of telomeric DNA in ten1 plants, likely via deletional recombination. Second, we show that AtTEN1 has the properties of a heat-shock induced molecular chaperone. At elevated temperature, AtTEN1 rapidly assembles into high molecular weight homo-oligomeric complexes that efficiently suppress heat-induced aggregation of model protein substrates in vitro. Finally, we report that AtTEN1 specifically protects CTC1 from heat-induced aggregation in vitro, and from heat-induced protein degradation and loss of telomere association in vivo. Collectively, these observations define Arabidopsis TEN1 as a highly dynamic protein that works in concert with CTC1 to preserve telomere integrity in response to environmental stress.

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Telomeres are partly shielded from ultraviolet-induced damage and proficient for nucleotide excision repair of photoproducts

Cited by 32 publications

References 61 publications

Oxidative guanine base damage regulates human telomerase activity

Oxidative guanine base damage regulates human telomerase activity

Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway

Dynamic Interactions of Arabidopsis TEN1: Stabilizing Telomeres in Response to Heat Stress

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