Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase–deficient mice and primary cells despite increased chromosomal instability
Enrique Samper,Fermín A. Goytisolo,Josiane Ménissier-de Murcia,Eva González-Suárez,Juan C. Cigudosa,Gilbert de Murcia,Maria A. Blasco +6 more
TLDR
The results presented here indicate that PARp-1 does not play a major role in regulating telomere length or in telomeric end capping, and the chromosomal instability of PARP-1−/− primary cells can be explained by the repair defect associated to PARP -1 deficiency.Abstract:
Poly(ADP-ribose) polymerase (PARP)-1, a detector of single-strand breaks, plays a key role in the cellular response to DNA damage. PARP-1-deficient mice are hypersensitive to genotoxic agents and display genomic instability due to a DNA repair defect in the base excision repair pathway. A previous report suggested that PARP-1-deficient mice also had a severe telomeric dysfunction consisting of telomere shortening and increased end-to-end fusions (d'Adda di Fagagna, F., M.P. Hande, W.-M. Tong, P.M. Lansdorp, Z.-Q. Wang, and S.P. Jackson. 1999. NAT: Genet. 23:76-80). In contrast to that, and using a panoply of techniques, including quantitative telomeric (Q)-FISH, we did not find significant differences in telomere length between wild-type and PARP-1(-/)- littermate mice or PARP-1(-/)- primary cells. Similarly, there were no differences in the length of the G-strand overhang. Q-FISH and spectral karyotyping analyses of primary PARP-1(-/)- cells showed a frequency of 2 end-to-end fusions per 100 metaphases, much lower than that described previously (d'Adda di Fagagna et al., 1999). This low frequency of end-to-end fusions in PARP-1(-/)- primary cells is accordant with the absence of severe proliferative defects in PARP-1(-/)- mice. The results presented here indicate that PARP-1 does not play a major role in regulating telomere length or in telomeric end capping, and the chromosomal instability of PARP-1(-/)- primary cells can be explained by the repair defect associated to PARP-1 deficiency. Finally, no interaction between PARP-1 and the telomerase reverse transcriptase subunit, Tert, was found using the two-hybrid assay.read more
Citations
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Natural and pharmacological regulation of telomerase
Jean-Louis Mergny,Jean-François Riou,Patrick Mailliet,Marie-Paule Teulade-Fichou,Eric Gilson +4 more
TL;DR: Telomeres and telomerase may be proposed as attractive targets for the discovery of new anticancer agents because of their specialised structures when it comes to replicating the DNA.
Journal ArticleDOI
Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination
TL;DR: The data suggest that PARP-1 controls DNA damage recognised by HR and that it is not involved in executing HR as such.
Journal ArticleDOI
Functional links between telomeres and proteins of the DNA-damage response
TL;DR: The current knowledge of both the telomere and the DDR are discussed, and an integrated model for the events associated with the metabolism of DNA ends in these two distinct physiological contexts are proposed.
Journal ArticleDOI
The telomerase activator TA-65 elongates short telomeres and increases health span of adult old mice without increasing cancer incidence
Bruno Bernardes de Jesus,Kerstin Schneeberger,Elsa Vera,Agueda M. Tejera,Calvin B. Harley,Maria A. Blasco +5 more
TL;DR: TA‐65 dietary supplementation in female mice leads to an improvement of certain health‐span indicators including glucose tolerance, osteoporosis and skin fitness, without significantly increasing global cancer incidence.
Journal ArticleDOI
The impact of oxidative DNA damage and stress on telomere homeostasis.
TL;DR: The studies demonstrating associations between oxidative stress and accelerated telomere attrition in human tissue, mice and cell culture are reviewed, and possible mechanisms and cellular pathways that protect telomeres from oxidative damage are discussed.
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TL;DR: Electron microscopy reported here demonstrated that TRF2 can remodel linear telomeric DNA into large duplex loops (t loops) in vitro, which may provide a general mechanism for the protection and replication of telomeres.
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Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA
Maria A. Blasco,Maria A. Blasco,Han Woong Lee,M. Prakash Hande,Enrique Samper,Peter M. Lansdorp,Ronald A. DePinho,Carol W. Greider,Carol W. Greider +8 more
TL;DR: Results indicate that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice.
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Structure and function of telomeres
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