Regulation of Telomere Length and Suppression of Genomic Instability in Human Somatic Cells by Ku86

Abstract

Ku86 plays a key role in nonhomologous end joining in organisms as evolutionarily disparate as bacteria and humans. In eukaryotic cells, Ku86 has also been implicated in the regulation of telomere length although the effect of Ku86 mutations varies considerably between species. Indeed, telomeres either shorten significantly, shorten slightly, remain unchanged, or lengthen significantly in budding yeast, fission yeast, chicken cells, or plants, respectively, that are null for Ku86 expression. Thus, it has been unclear which model system is most relevant for humans. We demonstrate here that the functional inactivation of even a single allele of Ku86 in human somatic cells results in profound telomere loss, which is accompanied by an increase in chromosomal fusions, translocations, and genomic instability. Together, these experiments demonstrate that Ku86, separate from its role in nonhomologous end joining, performs the additional function in human somatic cells of suppressing genomic instability through the regulation of telomere length.

We thank Richard Wang and Titia de Lange (The Rockefeller University) for the TRF protocols and Bert Vogelstein (The Johns Hopkins University) for the HCT116 p53-null cell line. Jamie Borton provided some preliminary data for the TRF studies. We are indebted to Judith Berman and Anja-Katrin Bielinsky (University of Minnesota) and David Bodine and Jennifer Puck (National Institutes of Health) for helpful discussions and comments on the manuscript. We are grateful to Maria Blasco (Spanish National Cancer Center) for communicating results prior to publication.