Mismatch repair as a source of mutations in non-dividing cells.

This paper describes a mechanism which permits somatic cells to generate random mutations in the complete absence of cell proliferation. The mechanism itself is remarkably simple, involving a well-known cellular process (mismatch repair or MMR) which is primarily associated with mutation avoidance, but which is also capable of generating mutations when circumstances are not ideal for avoidance. When MMR operates in its so-called 'methylation-instructed' mode to remove mismatches from newly-replicated portions of genomic DNA, it does so in a way which serves to minimize mutation yields. By contrast, when MMR operates in a non-instructed or 'randomly-templated' way to remove mismatches from DNA molecules, it does so without distinguishing between the two strands of DNA that contain the mismatched bases. Randomly-templated mismatch repair (RT-MMR) therefore generates new and complete mutations whenever it removes the correct bases from either base-pair mismatches or frameshift mispairs and replaces them without incorrect bases or sequences. Wider recognition of the existence of this mechanism--and especially of its proclivity for mutation generation when it is operating in non-dividing cells--should help us to develop a better understanding of a number of important biological phenomena, and may be of particular value in our attempts to explain the origins of many human cancers.