Figure 2.

Hypothetical model for the end-joining mechanisms during CSR. AID initiates CSR, probably through deamination of deoxycytidine (dC) residues in the S regions. The dC:dU mismatches can then be processed by either the MSH2-dependent mismatch repair pathway or the UNG-dependent base excision repair, leading to the production of DSBs in the S regions. In the predominant NHEJ pathway, Ku70/Ku80 binds to DNA ends and recruits and activates DNA-PKcs. They are probably important for the synapsis process. ATM and ATM-dependent factors γH2AX, MDC1 and 53BP1 are required for the predominant NHEJ pathway, probably at the synapsis or end-activation step. Together they may be configurating the DNA termini for subsequent repair steps and/or regulating the cell cycle response. ATM may also have a direct role in the end-processing step by phosphorylation of Artemis, a nuclease that may have the potential to repair a subset of DSBs in CSR. The Mre11 complex may be involved in CSR either by activating ATM and/or as a nuclease that is required for the microhomology-mediated end joining. Finally, XRCC4/DNA ligase IV and possibly XLF are involved in the ligation step. The factors involved in the A-EJ are not known but a few candidates are highlighted in the figure (indicated by question marks). (a) Predominant NHEJ, (b) alternative end joining.