Increased error-prone non homologous DNA end-joining--a proposed mechanism of chromosomal instability in Bloom's syndrome

Oncogene. 2002 Apr 11;21(16):2525-33. doi: 10.1038/sj.onc.1205331.


BS is an inherited cancer predisposition disorder caused by inactivation of the RecQ family helicase, BLM. One of the defining features of cells from BS individuals is chromosomal instability, characterized by elevated sister chromatid exchanges (SCEs), as well as chromosomal breaks, deletions, and rearrangements. Although the basis for chromosomal instability is poorly understood, there is evidence that chromosomal abnormalities can arise through an alteration in the efficiency or fidelity of DNA double strand break (DSB) repair. Here, we show that BS cells demonstrate aberrant DSB repair mediated by the non-homologous end-joining (NHEJ) pathway for DNA repair, one of the two main pathways for the repair of DSBs in mammalian cells. Through a comparison of BS cell lines, and a derivative in which the BS phenotype has been reverted by expression of the BLM cDNA, we show that BS cells display aberrant end-joining of DSBs. Importantly, DNA end-joining in BS cells is highly error-prone and frequently results in DNA ligation at distant sites of microhomology, creating large DNA deletions. This aberrant repair is dependent upon the presence of the Ku70/86 heterodimer, a key component in the NHEJ pathway. We propose that aberrant NHEJ is a candidate mechanism for the generation of chromosomal instability in BS.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / immunology
  • Antigens, Nuclear*
  • Base Sequence
  • Bloom Syndrome / genetics*
  • Bloom Syndrome / metabolism
  • Cell Line
  • Cells, Cultured
  • Chromosome Aberrations*
  • DNA Helicases*
  • DNA Repair*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / physiology
  • Humans
  • Ku Autoantigen
  • Nuclear Proteins / analysis
  • Nuclear Proteins / immunology
  • Nuclear Proteins / physiology
  • Recombination, Genetic


  • Antibodies
  • Antigens, Nuclear
  • DNA-Binding Proteins
  • Nuclear Proteins
  • DNA Helicases
  • XRCC5 protein, human
  • Xrcc6 protein, human
  • Ku Autoantigen