Coordinating Multi-Protein Mismatch Repair by Managing Diffusion Mechanics on the DNA

• Published in: Journal of molecular biology 2018-10, Vol.430 (22), p.4469-4480
• Main Authors: Kim, Daehyung, Fishel, Richard, Lee, Jong-Bong
• Format: Article
• Language: English
• Subjects: Animals; Biophysical Phenomena; Diffusion; diffusivity; DNA - metabolism; DNA Mismatch Repair; Humans; multiple proteins; Multiprotein Complexes - metabolism; single-molecule imaging; Stochastic Processes; stochasticity; Thermodynamics
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2018.05.032

DNA mismatch repair (MMR) corrects DNA base-pairing errors that occur during DNA replication. MMR catalyzes strand-specific DNA degradation and resynthesis by dynamic molecular coordination of sequential downstream pathways. The temporal and mechanistic order of molecular events is essential to insure interactions in MMR that occur over long distances on the DNA. Biophysical real-time studies of highly conserved components on mismatched DNA have shed light on the mechanics of MMR. Single-molecule imaging has visualized stochastically coordinated MMR interactions that are based on thermal fluctuation-driven motions. In this review, we describe the role of diffusivity and stochasticity in MMR beginning with mismatch recognition through strand-specific excision. We conclude with a perspective of the possible research directions that should solve the remaining questions in MMR. [Display omitted] •MSH (MutS homologs) bound to a mispaired nucleotide switches its conformation to a sliding clamp by ATP binding.•Freely diffusing ATP-bound MSH sliding clamp recruits MLH/PMS (MutL homologs).•The diffusing complex of ATP-bound MSH and MLH/PMS activates strand excision at a distant strand break.•ATP-bound MSH sliding clamp is a key player for the initiation and termination of DNA mismatch repair.•The stochastic coordination by thermal diffusion of mismatch repair components eventually results in robust repair events.