DNA mismatch repair: Dr. Jekyll and Mr. Hyde?

Abstract

In this issue, Peña-Diaz et al. (2012) describe a pathway for somatic mutation in nonlymphoid cells termed noncanonical DNA mismatch repair, whereby the error-prone translesion polymerase Pol-η substitutes for high-fidelity replicative polymerases to resynthesize excised regions opposite DNA damage.

Figure 1. Mutagenic and Nonmutagenic Outcomes of DNA Mismatch Repair

(A) General scheme for replication-linked MMR in which recognition of a mismatch by a MutSα-MutLα complex modulated by interaction with PCNA and ATP/ADP binding by MMR proteins licenses excision of the newly synthesized strand by EXO1 and an endonuclease function in the PMS2 subunit of MutLα. The resulting RPA-coated single-strand gap is a substrate for resynthesis by high-fidelity Pol-δ. (B) In activated B cells, AID creates G/U mispairs that are substrates for MutSα-MutLα. An ncMMR pathway is utilized in which mUbPCNA recruits Pol-η to carry out error-prone gap filling to achieve somatic hypermutation at variable regions of Ig genes. (C) A scenario for a ncMMR pathway operating in nonlymphoid cells that responds to a variety of DNA lesions that are substrates for MutSα including uracil, alkylated bases, and distorted DNA structures that impede replication. Recruitment of Pol-η by monoubiquitinated PCNA leads to error-prone gap filling.