Murine Models of Dysfunctional Telomeres and Telomerase

Liu, Yie; Harrington, Lea

doi:10.1002/9781118268667.ch9

Cited by 4 publications

(3 citation statements)

References 182 publications

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“…An age-associated increase in heterochromatic modifications has been noted in murine and primate models, but the role of telomeres in this process is still unknown [ 135 ]. The physiological consequence of DNA methylation changes induced by short telomeres could be tested in telomerase knockout mice, in which telomere loss culminates in wide-scale declines in stem cell and tissue function that lead to sterility and early mortality [ 136 ]. These changes are reversible via genetic or chemically inducible rescue of endogenous TERT expression, which results in re-extension of telomeres, reduced DNA damage signalling and associated cellular checkpoint responses and the amelioration of degenerative phenotypes in several tissues including brain, testes, spleen and intestines [ 137 – 139 ].…”

Section: Potential Implications For Cancer Cell Differentiationmentioning

confidence: 99%

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

Harrington

Pucci

2018

Phil. Trans. R. Soc. B

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The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones. Although the catastrophic consequences of full telomere de-protection are well described, recent evidence points to other, less obvious perturbations that arise when telomere length equilibrium is altered. For example, critically short telomeres also perturb DNA methylation and histone post-translational modifications at distal sites throughout the genome. In murine stem cells for example, this dysregulated chromatin leads to inappropriate suppression of pluripotency regulator factors such as Nanog. This review summarizes these recent findings, with an emphasis on how these genome-wide, telomere-induced perturbations can have profound consequences on cell function and fate.This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.

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Section: Potential Implications For Cancer Cell Differentiationmentioning

confidence: 99%

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

Harrington

Pucci

2018

Phil. Trans. R. Soc. B

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“…Mounting evidence supports the notion that telomere dysfunction primarily affects the hematopoietic lineage in both human and mice, suggesting the importance of telomere maintenance in highly proliferating cells (39,40). Because of the long arrays of TTAGGG repeats, telomeres might be susceptible to misincorporation of uracil.…”

Section: Discussionmentioning

confidence: 90%

“…Mounting evidence supports the notion that telomere dysfunction primarily affects the hematopoietic lineage in both humans and mice (39,40). We therefore examined telomere length in primary bone marrow cells from Ung Ϫ/Ϫ mice by Q-FISH (Fig.…”

Section: Uracil Accumulation Due To Defective Removal Disrupts Telomementioning

confidence: 98%

Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Vallabhaneni

Zhou

Maul

et al. 2015

Journal of Biological Chemistry

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Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo

et al. 2023

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Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert−/−) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert−/− mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert−/− hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert−/− transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.

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Murine Models of Dysfunctional Telomeres and Telomerase

Cited by 4 publications

References 182 publications

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo

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