Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models.
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.
Franco
Sonia
S
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Canela
Andrés
A
Klatt
Peter
P
Blasco
María A
MA
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D012016:Reference Values; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*; D014158:Transcription, Genetic
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D019098:Telomerase; C000606512:Xrcc5 protein, mouse; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen