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

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

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CNRS, Centre de Génétique Moléculaire, UPR3404, Gif-sur-Yvette, France ; CNRS, Centre de Recherches de Gif-sur-Yvette, FRC3115, Gif-sur-Yvette, France ; Université Paris-Sud, Département de Biologie, Orsay, France.
CEA, DSV, Institut de Radiobiologie Moléculaire et Cellulaire, Laboratoire Réparation et Vieillissement, Fontenay-aux-Roses, France ; UMR 8200 CNRS, Villejuif, France.
Université Paris-Sud, Département de Biologie, Orsay, France ; UMR 8200 CNRS, Villejuif, France ; Institut de Cancérologie, Gustave Roussy, Villejuif, France.


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.

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