Cells often arrange complex enzymatic reactions using organelles and phase separation. But for specific interactions with signal or enzymatic target sites, such as in DNA processing pathways, smaller but ordered high-specificity structures can be used. We have only scratched the surface in identifying how protein structures signal across distances on DNA strands, but our work characterizing a new model suggests how signals can be relayed through protein complexes and illuminates the mechanism of an essential biological process of DNA mismatch repair. Using combinations of biochemistry, biophysics, and molecular biology, our work indicates that the DNA mismatch repair endonuclease MutLalpha is regulated by DNA topology to initiate DNA repair at a site distant from the DNA error. Failures in this process are linked to a hereditary cancer syndrome, Lynch Syndrome, that affects approximately one in every three hundred individuals. Our data aid in our understanding of DNA repair and how failures contribute to human cancers and genome instability. Our work also informs models for other pathways that require action at a distance as well as systems that use mismatch repair proteins. These include trinucleotide repeat expansions which are linked to human neurological disorders, recombination which is linking to genetic variation and stability, and somatic hypermutation which can utilize mismatches formed by activation-induced cytosine deaminase to switch the class of immunoglobulins to adapt the immune system.
Support or Funding Information
S.J.W., I.M.R., and C.M.M. are supported by the Department of Chemistry and the College of Science and Technology at Temple University and by the National Institute of General Medical Sciences of the National Institutes of Health: R35GM142651.
