Fig. 5.

An integrated model for SHM. DSBs target V(D)J, BCL6, and c-MYC genes and initiate the process that leads to the introduction of somatic mutations through error-prone repair. In germline V and c-MYC genes of hypermutating or nonhyper-mutating B cells and in BCL6 of nonhypermutating B cells, DSBs are blunt and are repaired through NHEJ in a faultless fashion (a). In hypermutating rearranged V(D)J genes or germline BCL6 or c-MYC translocated into the Ig locus, blunt DSBs are either similarly resolved (a) or are modified in a CD40-induced and AID-dependent fashion to yield 5′- and 3′-protruding DNA ends. Other resected DSBs may also be generated as such. Generation of resected DSBs as such or through modification of blunt DSBs would occur through intervention of an AID-edited endonuclease and/or exonuclease or direct AID-dependent deamination. 3′-Recessed termini may be filled in by an error-free DNA polymerase (in absence of BCR cross-linking) (b) or by an error-prone DNA polymerase (upon BCR cross-linking) with introduction of mismatches (c), and then resolved by NHEJ. 3′-Protruding ends can invade sister chromatid strands and initiate a HR process which, upon BCR cross-linking, involves the activity of the translesion DNA polymerase ζ. Polymerase ζ, possibly in concern with polymerase ι, extends DNA strands past mispair, eventually leading to SHM (d). In the absence of BCR cross-linking, HR proceeds in an error-free fashion (e). DSBs do not target C regions and no mutations can be introduced in this DNA (f)