TY - JOUR
T1 - Effectors of mammalian telomere dysfunction
T2 - A comparative transcriptome analysis using mouse models
AU - Franco, Sonia
AU - Canela, Andrés
AU - Klatt, Peter
AU - Blasco, María A.
N1 - Funding Information:
We thank A.Benguría and staff at the CNB Affymetrix Core Facility for technical assistance, R.Serrano for mouse care, E.Santos and J.Freire for genotyping, and M.Serrano for critical comments on the manuscript. M.A.B.’s laboratory is funded by the MCyT (SAF2001-1869, GEN2001-4856-C13-08), CAM (08.1/0054/01), European Union (TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-CT-2003-508842) and the Josef Steiner Award 2003. S.F. is a Predoctoral Fellow of the Fondo de Investiga-ciones Sanitarias (FIS), Instituto de Salud Carlos III.
PY - 2005/9
Y1 - 2005/9
N2 - 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.
AB - 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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U2 - 10.1093/carcin/bgi107
DO - 10.1093/carcin/bgi107
M3 - Article
C2 - 15860505
AN - SCOPUS:24144473952
SN - 0143-3334
VL - 26
SP - 1613
EP - 1626
JO - Carcinogenesis
JF - Carcinogenesis
IS - 9
ER -