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Molecular and Cellular Biology, June 2004, p. 5050-5059, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.5050-5059.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Kyungjae Myung,¹ Goutam Ghosh,² Farjana J. Fattah,² Gang Li,^2, Haeyoung Kim,² Amalia Dutia,³ Evgenia Pak,³ Stephanie Smith,¹ and Eric A. Hendrickson^2*

Genome Instability Section, Genetics & Molecular Biology Branch,¹ Cytogenetic and Confocal Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892,³ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455²

Received 11 September 2003/ Returned for modification 24 October 2003/ Accepted 6 February 2004

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.

Present address: The Children's Hospital, Harvard Medical School, Boston, MA 02115.

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