Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways

FASEB J. 2011 Nov;25(11):3849-60. doi: 10.1096/fj.11-185546. Epub 2011 Jul 21.


Ataxia telangiectasia mutated (ATM) has multiple functions in homologous recombination (HR) and nonhomologous end joining (NHEJ), which lead to conflicting data regarding its DNA double-strand break-repair (DSBR) functions in previous studies. To explore the effect of clinically relevant ATM mutations, we characterized DSBR between mutated EGFP genes and ATM kinase signaling in 9 lymphoblastoid cell lines (LCLs) derived from patients with ataxia telangiectasia (AT) with defined vs. 3 control LCLs without ATM mutations. Our study revealed that the DSBR phenotype in AT cells is not uniform but appears to depend on the mutation, causing up to 32-fold increased or up to 3-fold decreased activities in particular pathways. Comparison with a further 10 LCLs mutated in downstream factors (BRCA1, BRCA2, Nibrin, Rad50, and Chk2) showed that the most diametrically opposed DSBR patterns in AT cells phenocopied NBN/RAD50 or BRCA1 mutations. Notably, reexpressing wild-type ATM reversed these defects by 2.3- to 3.5-fold. Our data suggest that ATM stimulates repair proteins such as Nibrin, which execute HR, single-strand annealing (SSA), and NHEJ. Concomitantly, ATM minimizes error-prone repair (SSA and NHEJ) through activation of surveillance factors such as BRCA1. Since the outcome of the individual defect can be diametrically opposed, distinguishing repair patterns in patients with ATM mutations may also be relevant regarding therapeutic responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein / genetics
  • BRCA1 Protein / physiology
  • BRCA2 Protein / genetics
  • Breast Neoplasms / genetics
  • Cell Cycle Proteins / genetics*
  • Cell Line
  • DNA Breaks, Double-Stranded
  • DNA Damage / genetics
  • DNA Repair / genetics*
  • DNA-Binding Proteins / genetics*
  • Down-Regulation
  • Female
  • Humans
  • Nuclear Proteins / genetics
  • Protein Serine-Threonine Kinases / genetics*
  • Signal Transduction / physiology
  • Tumor Suppressor Proteins / genetics*
  • Up-Regulation


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • NBN protein, human
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases