title: Cascading MutS and MutL sliding clamps control DNA diffusion to activate mismatch repair.
abstract: Mismatched nucleotides arise from polymerase misincorporation errors, recombination between heteroallelic parents and chemical or physical DNA damage. Highly conserved MutS (MSH) and MutL (MLH/PMS) homologues initiate mismatch repair and, in higher eukaryotes, act as DNA damage sensors that can trigger apoptosis. Defects in human mismatch repair genes cause Lynch syndrome or hereditary non-polyposis colorectal cancer and 10-40% of related sporadic tumours. However, the collaborative mechanics of MSH and MLH/PMS proteins have not been resolved in any organism. We visualized Escherichia coli (Ec) ensemble mismatch repair and confirmed that EcMutS mismatch recognition results in the formation of stable ATP-bound sliding clamps that randomly diffuse along the DNA with intermittent backbone contact. The EcMutS sliding clamps act as a platform to recruit EcMutL onto the mismatched DNA, forming an EcMutS-EcMutL search complex that then closely follows the DNA backbone. ATP binding by EcMutL establishes a second long-lived DNA clamp that oscillates between the principal EcMutS-EcMutL search complex and unrestricted EcMutS and EcMutL sliding clamps. The EcMutH endonuclease that targets mismatch repair excision only binds clamped EcMutL, increasing its DNA association kinetics by more than 1,000-fold. The assembly of an EcMutS-EcMutL-EcMutH search complex illustrates how sequential stable sliding clamps can modulate one-dimensional diffusion mechanics along the DNA to direct mismatch repair.
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Jeungphill
authors.initials: J
authors.lastname: Hanne
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Britton
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Department of Physics, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk 790-784, Korea.
authors.forename: Daehyung
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Physics, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk 790-784, Korea.|School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Kyungbuk, 790-784, Korea.
authors.forename: Jong-Bong
authors.initials: JB
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.|Department of Physics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Fishel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004058:Diffusion; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004720:Endonucleases / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D000070956:MutL Proteins / Q000737:chemistry / Q000378:metabolism*; D051719:MutS DNA Mismatch-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D000072760:Single Molecule Imaging
chemical_list: D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D046912:Multiprotein Complexes; D000255:Adenosine Triphosphate; D004247:DNA; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C059682:methyl-directed mismatch repair protein, E coli; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; D045643:DNA Repair Enzymes