Journal Article

Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models

Sonia Franco, Andrés Canela, Peter Klatt and María A. Blasco

in Carcinogenesis

Volume 26, issue 9, pages 1613-1626
Published in print September 2005 | ISSN: 0143-3334
Published online April 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi107
Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models

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Critical telomere shortening in the absence of telomerase in late generation Terc−/− mice (G3 Terc−/−) or loss of telomere capping due to abrogation of the DNA repair/telomere binding protein Ku86 (Ku86−/− mice) results in telomere dysfunction and organismal premature aging. Here, we report on genome-wide transcription in mouse G3 Terc−/−, Ku86−/− and G3 Terc−/−/Ku86−/− germ cells using high-density oligonucleotide microarrays. Although a few transcripts are modulated specifically in Ku86- or Terc-deficient cells, the observed transcriptional response is mainly inductive and qualitatively similar for all three genotypes, with highest transcriptional induction observed in double mutant G3 Terc−/−/Ku86−/− cells compared with either single mutant. Analysis of 92 known genes induced in G3 Terc−/−/Ku86−/− germ cells compared with wild-type cells shows predominance of genes involved in cell adhesion, cell-to-cell and cell-to-matrix communication, as well as increased metabolic turnover and augmented antioxidant responses. In addition, the data presented in this study support the view that telomere dysfunction induces a robust compensatory response to rescue impaired germ cell function through the induction of survival signals related to the PI3-kinase pathway, as well as by the coordinated upregulation of transcripts that are essential for mammalian spermatogenesis.

Keywords: ATM, ataxia telangiectasia; Cdk5, cyclin-dependent protein kinase-5; CTGF, connective tissue growth factor; DM, double mutant; DSB, double strand break; ECM, extracellular matrix; qRT-PCR, quantitative real-time PCR; RT, reverse transcription; SM, single mutants; Terc, telomerase RNA component

Journal Article.  7060 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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