Modeling non-homologous end joining

Non-homologous end joining (NHEJ) is an important DNA repair pathway for DNA double-strand breaks. Several proteins, including Ku, DNA-PKcs, Artemis, XRCC4/Ligase IV and XLF, are involved in the NHEJ for the DNA damage detection, DNA free end processing and ligation. The classical model of NHEJ is a sequential model in which DNA-PKcs is first recruited by the Ku bound DNA prior to any other repair proteins. Recent experimental study (McElhinny et al., 2000, Costantini et al., 2007, Mari et al., 2006 and Yano and Chen, 2008) suggested that the recruitment ordering is not crucial. In this work, by proposing a mathematical model in terms of biochemical reaction network and performing stability and related analysis, we demonstrate theoretically that if DSB repair pathway independent of DNA-PKcs exists, then the classical sequential model and new two-phase model are essentially indistinguishable in the sense that DSB can be repaired thoroughly in both models when the repair proteins are sufficient.

► The non-homologous end-joining pathway is the predominant pathway for double-strand break repair in mammalian cells.
► We describe the most comprehensive model of NHEJ than has been considered to date.
► A detailed stability analysis of the system is described.
► Analysis is performed to consider possible orders of assembly of repair proteins, and the possible outcomes on repair.