Is non-homologous end-joining really an inherently error-prone process?

PLoS Genet. 2014 Jan;10(1):e1004086. doi: 10.1371/journal.pgen.1004086. Epub 2014 Jan 16.


DNA double-strand breaks (DSBs) are harmful lesions leading to genomic instability or diversity. Non-homologous end-joining (NHEJ) is a prominent DSB repair pathway, which has long been considered to be error-prone. However, recent data have pointed to the intrinsic precision of NHEJ. Three reasons can account for the apparent fallibility of NHEJ: 1) the existence of a highly error-prone alternative end-joining process; 2) the adaptability of canonical C-NHEJ (Ku- and Xrcc4/ligase IV-dependent) to imperfect complementary ends; and 3) the requirement to first process chemically incompatible DNA ends that cannot be ligated directly. Thus, C-NHEJ is conservative but adaptable, and the accuracy of the repair is dictated by the structure of the DNA ends rather than by the C-NHEJ machinery. We present data from different organisms that describe the conservative/versatile properties of C-NHEJ. The advantages of the adaptability/versatility of C-NHEJ are discussed for the development of the immune repertoire and the resistance to ionizing radiation, especially at low doses, and for targeted genome manipulation.

Publication types

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

MeSH terms

  • DNA Breaks, Double-Stranded / radiation effects
  • DNA Damage / immunology
  • DNA Damage / radiation effects
  • DNA End-Joining Repair / genetics*
  • DNA End-Joining Repair / immunology
  • DNA Ligases
  • DNA Repair / genetics*
  • DNA Repair / immunology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Genomic Instability*
  • Radiation, Ionizing
  • Recombination, Genetic / immunology


  • DNA-Binding Proteins
  • XRCC4 protein, human
  • DNA Ligases

Grant support

BSL was supported through funding from the Fondation ARC (Association pour la Recherche contre le Cancer) and the INCa (Institut National du Cancer). MB was supported by core funding from the CNRS and by grants from the ANR (Agence Nationale de la Recherche: grants ANR BLAN08-3-310945 and ANR 2010-BLAN-1603) and the Fondation ARC. PB was supported by grants from Fondation ARC, Ligue Contre le Cancer-Comité Ile de France and by intramural funding “Radiobiology” from CEA-DSV. The funders had no role in the preparation of the article.