Tpp1/Acd maintains genomic stability through a complex role in telomere protection

Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology
Tobias ElseDavid O Ferguson

Abstract

Telomeres serve to protect the ends of chromosomes, and failure to maintain telomeres can lead to dramatic genomic instability. Human TPP1 was identified as a protein which interacts with components of a telomere cap complex, but does not directly bind to telomeric DNA. While biochemical interactions indicate a function in telomere biology, much remains to be learned regarding the roles of TPP1 in vivo. We previously reported the positional cloning of the gene responsible for the adrenocortical dysplasia (acd) mouse phenotype, which revealed a mutation in the mouse homologue encoding TPP1. We find that cells from homozygous acd mice harbor chromosomes fused at telomere sequences, demonstrating a role in telomere protection in vivo. Surprisingly, our studies also reveal fusions and radial structures lacking internal telomere sequences, which are not anticipated from a simple deficiency in telomere protection. Employing spectral karyotyping and telomere FISH in a combined approach, we have uncovered a striking pattern; fusions with telomeric sequences involve nonhomologous chromosomes while those lacking telomeric sequences involve homologues. Together, these studies show that Tpp1/Acd plays a vital role in telomere protection, b...Continue Reading

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