Abstract
Mismatch Repair (MMR) is an important and conserved keeper of the maintenance of genetic information. Miroslav Radman’s contributions to the field of MMR are multiple and tremendous. One of the most notable was to provide, along with Bob Wagner and Matthew Meselson, the first direct evidence for the existence of the methyl-directed MMR. The purpose of this review is to outline several aspects and biological implications of MMR that his work has helped unveil, including the role of MMR during replication and recombination editing, and the current understanding of its mechanism. The review also summarizes recent discoveries related to the visualization of MMR components and discusses how it has helped shape our understanding of the coupling of mismatch recognition to replication. Finally, the author explains how visualization of MMR components has paved the way to the study of spontaneous mutations in living cells in real time.
Highlights
The MMR system is an important DNA-repair process found in all three domains of life
Loss of its activity results in up to a thousand-fold increase in spontaneous point mutation rate, an increase in recombination, and high instability of short repeated sequences in organisms ranging from bacteria to humans
The observation of the latter phenotype [3,4] in some tumors led to the discovery that mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, i.e., Lynch syndrome [5,6,7,8,9] and a significant fraction of sporadic cancers [10]
Summary
The MMR system is an important DNA-repair process found in all three domains of life. During DNA replication, MMR detects errors of nucleotide incorporation in the DNA molecule (mismatches, small insertion, and deletion loops) and recruits enzymes to excise and resynthesize the portion of the newly synthesized strand containing the error. Like MutS, MutL is a weak homodimeric GHKL family ATPase [49,50] It binds to MutS, which requires mismatch and ATP [51,52,53] and to downstream components MutH and UvrD, which allows their activation and the initiation of downstream steps [54] (Figure 1). Eukaryotic MMR does not require helicases and relies on Exonuclease I or replicative polymerase activity for strand excision and displacement
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