MutS sliding clamps on an uncertain track to DNA mismatch repair.

Mispairs in DNA are base pairs that violate Watson–Crick base-pairing rules or small insertions or deletions that affect only one strand. Most mispairs are DNA replication errors caused by incorporation of incorrect nucleotides or, more frequently, “slippage” of DNA polymerases on low-complexity sequences. Unrepaired mispairs alter RNA and protein sequences if the error affects the RNA polymerase template strand and cause heritable mutations when replicated. Defects in DNA mismatch repair (MMR) cause cancer predisposition syndromes in humans; inactivation of one copy of an MMR gene causes Lynch syndrome associated with increased incidence of many types of cancer, whereas inactivation of both copies causes constitutional mismatch repair deficiency associated with pediatric cancers. Some bacteria and archaea use the NucS nuclease to mediate MMR; NucS cleaves DNA at mispairs, which likely initiates homologous recombination with the other daughter strand (1). In most organisms, however, MMR directs resynthesis of the newly synthesized DNA strand around the mispair either following strand excision or potentially by promoting strand-displacement synthesis (2). This process is controlled by homologs of Escherichia coli MutS and MutL, which will be called “MutS” and “MutL” in this commentary instead of “MutS homolog” and “MutL homolog” for brevity. The fact that MutS recognizes mispairs and subsequently recruits MutL to mediate downstream events has been understood for decades. What is unclear, however, is how these steps work; both MutS and MutL form rings around the DNA and can act up to 2 kbp from the mispair in either direction. These complex action-at-a-distance properties have prompted studies by advanced biophysical techniques and led to a proliferation of models, including the “molecular switch/sliding clamp” and “MutL polymerization” models and the now disfavored “hydrolysis-dependent translocation” and “static transactivation” models (described in refs. 2 and 3). In PNAS, Hao et al. (4) use single-molecule fluorescence resonance energy … [↵][1]1Email: cdputnam{at}health.ucsd.edu. [1]: #xref-corresp-1-1