Fig. 4.

DNA polymerase ζ is regulated by BCR-signaling and plays a critical role in SHM, likely in concert with polymerase ι and concomitant with profound downregulation of polymerase η, as induced by BCR-signaling. Translesion DNA polymerase ι, polymerase η, and polymerase ζ are depicted in purple, yellow, and turquoise, respectively. The low processivity of polymerase η allows for extrinsic exonucleases to proofread the mismatched nucleotides it inserts. This together with the inability of polymerase η to elongate a DNA strand after incorporating the incorrect nucleotide opposite a lesion allows this polymerase to perform error-free translesion synthesis of damaged DNA. Polymerase ζ efficiently extends damaged DNA, in concert with the error-prone, low processivity polymerase ι, after the incorporation of one or two mismatched deoxynucleotides by this polymerase. Polymerase ι and polymerase ζ act sequentially: polymerase ι as a “mispair inserter” and polymerase ζ as “mispair extender,” and this lesion-bypass DNA synthesis is continued by polymerase δ and polymerase ε. BCR cross-linking also signals the upregulation of DNA polymerase ζ, thereby allowing for the mismatches inserted by polymerase ι to be efficiently extended, giving rise to a newly synthesized DNA strand containing point-mutations.