Telomeres: Hallmarks of radiosensitivity

Ayouaz, Ali; Raynaud, Christophe M.; Heride, Claire; Revaud, Deborah; Sabatier, Laure

doi:10.1016/j.biochi.2007.09.011

Cited by 74 publications

(67 citation statements)

References 131 publications

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“…S8). ALT is most efficient in S-and G 2 phase where the sister chromatids are available (34). Interestingly, Xpc À/À keratinocytes show a cellcycle arrest in late S-phase upon single UV exposure, both in vivo and in vitro (38,39).…”

Section: Discussionmentioning

confidence: 98%

“…It is envisaged that stalling of transcription or replication, unresolved repair intermediates, or even a collapse of the replication fork provokes genomic as well as telomere instability. Failure to repair DNA breaks and telomere shortening below critical length result into replicative senescence or cell death (34). Strikingly, no apparent signs of apoptosis were found in UV-exposed Xpc increase in proliferation, hyperplasia, and aberrant epidermal differentiation was observed ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

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Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C

Stout

Blasco

2013

Cancer Research

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Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional telomeres, including mice deficient for telomerase (Terc À/À mice). Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc-mutant mice and Xpc À/À G1-G3Terc À/À double-mutant mice and exposed them to UV radiation.Chronically UV-exposed Xpc À/À skin displayed shorter telomeres on an average compared with wild-type skin.Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc À/À G1-G3Terc À/À mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in telomere stability, particularly upon UV exposure. In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of telomere lengthening. Cancer Res; 73(6);

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C

Stout

Blasco

2013

Cancer Research

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“…Telomerase can play a role in the healing of chromosomes or chromatid breaks produced by this damage and, therefore, might enhance the radioresistance of cells. 16,17 Telomerase activity is controlled by the regulation of the catalytic subunit of telomerase (hTERT), through modulating the expression and posttranslational modifications of hTERT. 18 Expression of hTERT is tightly regulated at the transcriptional level and the hTERT promoter contains a variety of binding sites for both activating and inhibiting transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Targeting EBV-LMP1 DNAzyme enhances radiosensitivity of nasopharyngeal carcinoma cells by inhibiting telomerase activity

Yang

Liu

et al. 2013

Cancer Biology & Therapy

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“…While telomere length is closely correlated with cancer cell radiosensitivity (Ayouaz et al 2008). Another mechanism contributing to autocrine hGH-mediated radioresistance may be through the upregulation of telomerase (Emerald et al 2007).…”

Section: N M Bougen Et Al: Autocrine Human Gh Is Radioprotectivementioning

confidence: 99%

Autocrine human GH promotes radioresistance in mammary and endometrial carcinoma cells

Bougen¹,

Steiner²,

Pertziger³

et al. 2012

Endocrine-Related Cancer

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Although recent advances in breast cancer treatment regimes have improved patient prognosis, resistance to breast cancer therapies, such as radiotherapy, is still a major clinical challenge. In the current study, we have investigated the role of autocrine human GH (hGH) in resistance to ionising radiation (IR)-based therapy. Cell viability and total cell number assays demonstrated that autocrine hGH promoted cell regrowth in the mammary carcinoma cell lines, MDA-MB-435S and T47D, and the endometrial carcinoma cell line, RL95-2, following treatment with IR. In addition, autocrine hGH enhanced MDA-MB-435S and T47D cell clonogenic survival following radiation exposure. The enhanced clonogenic survival afforded by autocrine hGH was mediated by JAK2 and Src kinases. Investigation into the DNA repair capacity demonstrated that autocrine hGH reduced IR-induced DNA damage in MDA-MB-435S and T47D cells. Functional antagonism of hGH increased RL95-2 sensitivity to IR in cell viability and total cell number assays, reduced clonogenic survival and enhanced the induction of DNA damage. Thus, autocrine hGH reduced sensitivity to treatment with IR in mammary and endometrial carcinoma cell lines in vitro, while functional antagonism of hGH sensitised endometrial carcinoma cells to IR. Functional antagonism of hGH, used in conjunction with radiotherapy, may therefore enhance treatment efficacy and improve the prognosis of patients with breast and endometrial cancer.

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Telomeres: Hallmarks of radiosensitivity

Cited by 74 publications

References 131 publications

Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C

Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum C

Targeting EBV-LMP1 DNAzyme enhances radiosensitivity of nasopharyngeal carcinoma cells by inhibiting telomerase activity

Autocrine human GH promotes radioresistance in mammary and endometrial carcinoma cells

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