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DNA mismatch repair (MMR) requires coordinated sequential actions of multiple proteins during a window of time after the replication apparatus makes an error and before the newly synthesized DNA undergoes chromosome compaction and/or methylation of dGATC sites in some g-proteobacteria. In this review, we focus on the steps carried out by MutS and MutL homologs that initiate repair. We connect new structural data to early and recent single-molecule FRET and atomic force microscopy (AFM) studies to reveal insights into how signaling within the MMR cascade connects MutS homolog recognition of a mismatch to downstream repair. We present unified models of MMR initiation that account for the differences in the strand discrimination signals between methyl- and non-methyl- directed MMR. 

Dynamic mutations in some human genes containing trinucleotide repeats are associated with severe neurodegenerative and neuromuscular disorders—known as Trinucleotide (or Triplet) Repeat Expansion Diseases (TREDs)—which arise when the repeat number of triplets expands beyond a critical threshold. While the mechanisms causing the DNA triplet expansion are complex and remain largely unknown, it is now recognized that the expandable repeats lead to the formation of nucleotide configurations with atypical structural characteristics that play a crucial role in TREDs. These nonstandard nucleic acid forms include single-stranded hairpins, Z-DNA, triplex structures, G-quartets and slipped-stranded duplexes. Of these, hairpin structures are the most prolific and are associated with the largest number of TREDs and have therefore been the focus of recent single- molecule FRET experiments and molecular dynamics investigations. Here, we review the structural and dynamical properties of nucleic acid hairpins that have emerged from these studies and the implications for repeat expansion mechanisms. The focus will be on CAG, GAC, CTG and GTC hairpins and their stems, their atomistic structures, their stability, and the important role played by structural interrupts.