Figure 4.

Propensity for DSB Repair Processes in G1 Phase to Give Rise to Translocations. Repair of DSBs in G1 by end-joining mechanisms can give rise to translocations when the incorrect break ends are mis-rejoined. However, the propensity for the different end-joining processes to produce translocations differs. Compared with resection-independent c-NHEJ, which repairs the majority of X-ray-induced DSBs with fast kinetics, Artemis-dependent c-NHEJ has ∼4-fold higher potential to cause translocations after 7 Gy [8]. We stress that translocations arise with dose in a linear-quadratic manner and that the relative contribution of the fast and slow repair processes may depend on dose. This increased propensity for translocation formation is likely the result of resection since preventing the initiation of resection by siRNA-mediated CtIP depletion significantly decreases translocation formation [13]. We speculate that DSBs undergoing resection are normally stabilized by bridging factors (depicted as purple brackets) whose occasional release from the ends can cause translocations. Chromatin compaction factors and/or DNA-PK bound to the ends may serve as such bridging factors. Alt-NHEJ processes, which do not seem to make an appreciable contribution to DSB repair in G0/G1-phase human cells (and are hence displayed by a dashed line), have a high potential to cause translocations in mouse cells. The figure shows all DSBs being repaired by alt-NHEJ since we do not know the contribution of alt-NHEJ versus c-NHEJ in mouse cells. The relative contributions of the three processes for DSB repair and the propensity for translocation formation are shown on the right. Alt-NHEJ, alternative nonhomologous end joining; c-NHEJ, canonical nonhomologous end joining; DNA-PK, DNA-dependent protein kinase; DSB, double-strand break.