Ku86 represses lethal telomere deletion events in human somatic cells

Yongbao Wang, Goutam Ghosh, Eric A Hendrickson

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

Nonhomologous end joining (NHEJ), a form of DNA double-strand break (DSB) repair, is conserved from bacteria to humans. One essential NHEJ factor is Ku, which consists of a heterodimer of Ku70 and Ku86. In a plethora of model systems, null mutations for Ku70 or Ku86 present with defects in DNA DSB repair, variable(diversity)joining [V(D)J] recombination, and/or telomere maintenance. The complete loss of Ku from bacteria to mice is, however, compatible with viability. In striking contrast, human patients with mutations of either Ku subunit have never been described. Here, we have used recombinant adeno-associated virus-mediated gene targeting to produce a human somatic cell line that expresses a conditionally null allele of Ku86. The induced loss of Ku86 results in cell death accompanied by massive telomere loss in the form of t-circles. Thus, Ku86 is an essential gene in human somatic cells because of its requirement, not in NHEJ or V(D)J recombination, but in telomere maintenance.

Original languageEnglish (US)
Pages (from-to)12430-12435
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number30
DOIs
StatePublished - Jul 28 2009

Keywords

  • DNA-PK
  • Homologous recombination
  • NHEJ
  • rAAV
  • t-circles

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