Loss of Telomere Protection: Consequences and Opportunities

Jacobs, Jacqueline J.L.

doi:10.3389/fonc.2013.00088

Cited by 23 publications

(14 citation statements)

References 77 publications

(80 reference statements)

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“…The ability of the telomeres to protect the chromosomes critically depends on the binding of sufficient quantities of functional shelterin, a 6-unit protein complex with specific and crucial roles in telomere maintenance and function. Insufficient telomere length, leading to insufficient concentration of shelterin at chromosome ends, or otherwise crippled shelterin function, causes telomere deprotection [ 9 ]. While contributing to aging-related pathologies, loss of telomere protection can act as a barrier to tumorigenesis, as dysfunctional telomeres activate DNA-damage-like checkpoint responses that halt cell proliferation or trigger cell death.…”

Section: Chronic Stress Cell Aging and Chromosomal Markersmentioning

confidence: 99%

“…While contributing to aging-related pathologies, loss of telomere protection can act as a barrier to tumorigenesis, as dysfunctional telomeres activate DNA-damage-like checkpoint responses that halt cell proliferation or trigger cell death. In addition, dysfunctional telomeres affect cancer development and progression by being a source of genomic instability [ 9 ].…”

Section: Chronic Stress Cell Aging and Chromosomal Markersmentioning

confidence: 99%

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Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length

Esch

Kream

Stefano

2018

Med Sci Monit Basic Res

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Stress affects cellular aging and inflammatory and chromosomal processes, including telomere length, thereby potentially compromising health and facilitating disease onset and progression. Stress-related diseases and strategies to manage stress usually require integrative or behavioral therapeutic approaches that also operate on cellular levels. Mind-body medicine (MBM) uses the interaction between the mind, body, behavior, and the environment to correct physical and psychological malfunctions, thus ameliorating disease states and improving health. The relaxation response (RR) is a physiological opponent of stress and the stress response (SR) (i.e., fight-or-flight response), also invoking molecular anti-stress processes. Techniques that elicit the RR are at the core of practically all MBM interventions. We surmise that these techniques can also affect chromosomal and telomere processes, molecular aging, and the modulation of inflammatory states on cellular levels.

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Section: Chronic Stress Cell Aging and Chromosomal Markersmentioning

confidence: 99%

Section: Chronic Stress Cell Aging and Chromosomal Markersmentioning

confidence: 99%

Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length

Esch

Kream

Stefano

2018

Med Sci Monit Basic Res

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“…The senescence normally prevents the replication of abnormal chromosomes. The p16/pRb tumor suppressor pathways are activated in response to DNA damage and telomere dysfunction during senescence [ 23 , 24 , 25 ]. This process, however, could be flawed by oncogene activation to bypass senescence.…”

Section: Telomeres and Telomerase In Aging And Cancermentioning

confidence: 99%

Therapeutic Targeting of Telomerase

Jäger

Walter

2016

Genes

124

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Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches. Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a ‘mild’ integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

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“…This work, and a companion report in this edition of the journal describing germline POT1 mutations in Italian, French and American families 20 , together with the recently described TERT promoter variant 2 , significantly extend our understanding of a novel mechanism predisposing to the development of familial melanoma. Since the dysregulation of telomere protection by POT1 has recently been identified as a target for potential therapeutic intervention 21 , it may be possible that early identification of families with POT1 variants may facilitate better management of their disease in the future.…”

mentioning

confidence: 99%

POT1 loss-of-function variants predispose to familial melanoma

et al. 2014

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Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.

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Loss of Telomere Protection: Consequences and Opportunities

Cited by 23 publications

References 77 publications

Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length

Chromosomal Processes in Mind-Body Medicine: Chronic Stress, Cell Aging, and Telomere Length

Therapeutic Targeting of Telomerase

POT1 loss-of-function variants predispose to familial melanoma

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