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Mismatch repair interactome and mutagenesis

Final Report Summary - MIRIAM (Mismatch repair interactome and mutagenesis)

This project was conceived on the basis of a discovery made by immunologists, who noted that the number and type of mutations induced in immunoglobulin genes during antibody maturation in mice lacking mismatch repair (MMR) genes differed from those found in wild type animals; the mutations were fewer in number and their positions were different. This finding was unexpected; it suggested that the MMR system, which has evolved to improve the fidelity of DNA synthesis, is required to induce mutations into immunoglobulin genes upon activation of the immune response by antigens.
We have set out to identify the molecular basis of this phenomenon and succeeded in discovering non-canonical MMR (nc-MMR), a process in which MMR is triggered in a phase of the cell cycle, when the enzymes and the building blocks required for error-free DNA synthesis are available in insufficient quantities. Under these circumstances, DNA synthesis can be error-prone (Pena-Diaz et al., Mol. Cell, 2013).
We have also been able to reconstitute the minimal system required for the initiation of this process from purified recombinant proteins (Bregenhorn et al., NAR, 2015, 2016).