Yeast Ku as a Regulator of Chromosomal DNA End Structure

Gravel, Serge; Larrivée, Michel; Labrecque, Pascale; Wellinger, Raymund J.

doi:10.1126/science.280.5364.741

Cited by 397 publications

(378 citation statements)

References 18 publications

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“…Thus if ATM has a role both in telomere maintenance (as suggested by a recent report (Smilenov et al, 1997)) as well as in DNA damage signalling, one might speculate that in fact both processes use the same machinery. Ku, a DNA break-binding protein, also plays a role in telomere maintenance (Gravel et al, 1998;Boulton and Jackson, 1998). Non-coding DNA regions such as the telomeres might be used by the cell as sensors for free radicals, detected under the form of DNA damage, taking advantage of the sensitiveness of DNA to chemical and physical agents.…”

Section: Discussionmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kB. It is activated by various stress situations, including oxidative stress, and by DNAdamaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NFkB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.

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Section: Discussionmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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“…In budding yeast, the Ku heterodimer is associated with telomeric DNA and maintains telomere integrity (Gravel et al, 1998). Ku de®ciency results in an altered telomere structure which appears to activate a DNA damage pathway at elevated temperature resulting in an inherent ts phenotype of Ku null strains (Barnes and Rio, 1997;Teo and Jackson, 2001).…”

Section: Comparison Of Telomere Deprotection In Mammals and Yeastmentioning

confidence: 99%

Protection of mammalian telomeres

2002

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Telomeres allow cells to distinguish natural chromosome ends from damaged DNA. When telomere function is disrupted, a potentially lethal DNA damage response can ensue, DNA repair activities threaten the integrity of chromosome ends, and extensive genome instability can arise. It is not clear exactly how the structure of telomere ends di ers from sites of DNA damage and how telomeres protect chromosome ends from DNA repair activities. What are the de®ning structural features of telomeres and through which mechanisms do they ensure chromosome end protection? What is the molecular basis of the telomeric cap and how does it act to sequester the chromosome end? Here I discuss data gathered in the last few years, suggesting that the protection of human chromosome ends primarily depends on the telomeric protein TRF2 and that telomere capping involves the formation of a higher order structure, the telomeric loop or t-loop.

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“…The Ku heterodimer is another important link between silencing and telomere function. In yeast, Ku associates with the telomere and has a role both in promoting telomerase activity (potentially by binding to telomerase RNA) and in telomeric silencing (Boulton and Jackson, 1998;Gravel et al, 1998;Mishra and Shore, 1999;Peterson et al, 2001).…”

Section: Heterochromatic Properties Of Telomeric Regionsmentioning

confidence: 99%

New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin

2002

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Telomeres are stabilized, and telomeric DNA is replenished, by the action of the ribonucleoprotein reverse transcriptase telomerase. Telomere capping functions include the ability of telomeres to protect chromosome ends from cellular DNA-damage responses such as cell cycle arrest or apoptosis. This property of telomeres is especially important for cancer cells, which continue proliferating despite chromosome aberrations. Telomere capping is in¯uenced by multiple, mutually reinforcing factors including telomere length, although telomere length is only one of several determinants of telomere functionality. For example, many cancer cells express high levels of telomerase yet maintain relatively short telomeres. We consider three aspects of telomere capping that have emerged relatively recently: (1) a new role for telomerase in telomere capping independent of its function in telomere elongation. Support for this novel function comes from experiments showing an increase in replicative potential with the reactivation of telomerase, without net telomere lengthening; (2) the role at telomeres of DNA damage proteins. We propose a model in which two factors speci®cally target telomeres for the action of telomerase, as opposed to recombination or non-homologous end-joining: binding by telomeric proteins that limits DNA damage responses at telomeres, and the a nity of the telomerase RNP for telomeric proteins and DNA; and (3) we discuss a potential protective role of ampli®ed subtelomeric DNAs, which may aid capping of telomeres maintained by nontelomerase based mechanisms through the formation of heterochromatin.

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Yeast Ku as a Regulator of Chromosomal DNA End Structure

Cited by 397 publications

References 18 publications

The ATM protein is required for sustained activation of NF-κB following DNA damage

The ATM protein is required for sustained activation of NF-κB following DNA damage

Protection of mammalian telomeres

New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin

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