Greenall A, Lei G, Swan DC, James K, Wang L, Peters H, Wipat A, Wilkinson DJ, Lydall D

BACKGROUND: Telomeres prevent the ends of eukaryotic chromosomes from being recognized as damaged DNA and protect against cancer and ageing. When telomere structure is perturbed, a co-ordinated series of events promote arrest of the cell cycle so that cells carrying damaged telomeres do not divide. In order to better understand ...

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the eukaryotic response to telomere damage, budding yeast strains harboring a temperature sensitive allele of an essential telomere capping gene (cdc13-1) were subjected to a transcriptomic study. RESULTS: The genome-wide response to uncapped telomeres in yeast cdc13-1 strains, which have telomere capping defects at temperatures above approximately 27 degrees C, was determined. Telomere uncapping in cdc13-1 strains is associated with the differential expression of over 600 transcripts. Transcripts affecting responses to DNA damage and diverse environmental stresses were statistically over-represented. BNA2, required for the biosynthesis of NAD+, is highly and significantly up-regulated upon telomere uncapping in cdc13-1 strains. We find that deletion of BNA2 and NPT1, which is also involved in NAD+ synthesis, suppresses the temperature sensitivity of cdc13-1 strains, indicating that NAD+ metabolism may be linked to telomere end protection. CONCLUSIONS: Our data support the hypothesis that the response to telomere uncapping is related to, but distinct from, the response to non-telomeric double-strand breaks. The induction of environmental stress responses may be a conserved feature of the eukaryotic response to telomere damage. BNA2, which is involved in NAD+ synthesis, plays previously unidentified roles in the cellular response to telomere uncapping.

Date: Oct. 03, 2008

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