Carcinogenesis Advance Access originally published online on April 28, 2005
Carcinogenesis 2005 26(9):1613-1626; doi:10.1093/carcin/bgi107
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Carcinogenesis vol.26 no.9 © Oxford University Press 2005; all rights reserved.
Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
* To whom correspondence should be addressed. Tel: +34 917328031; Fax: +34 917328028; Email: mblasco{at}cnio.es
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.
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