TY - JOUR T1 - A mechanism to minimize errors during non-homologous end joining JF - bioRxiv DO - 10.1101/563197 SP - 563197 AU - Benjamin M. Stinson AU - Andrew T. Moreno AU - Johannes C. Walter AU - Joseph J. Loparo Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/05/08/563197.abstract N2 - Enzymatic processing of DNA underlies all DNA repair, yet inappropriate DNA processing must be avoided. In vertebrates, double-strand breaks are repaired predominantly by non-homologous end-joining (NHEJ), which directly ligates DNA ends. NHEJ has the potential to be highly mutagenic because it employs DNA polymerases, nucleases, and other enzymes that modify incompatible DNA ends to allow their ligation. Using a biochemical system that recapitulates key features of cellular NHEJ, we show that end-processing requires formation of a “short-range synaptic complex” in which DNA ends are closely aligned in a ligation-competent state. Furthermore, single-molecule imaging directly demonstrates that processing occurs within the short-range complex. This confinement of end processing to a ligation-competent complex ensures that DNA ends undergo ligation as soon as they become compatible, thereby minimizing mutagenesis. Our results illustrate how the coordination of enzymatic catalysis with higher-order structural organization of substrate maximizes the fidelity of DNA repair. ER -