title: Conformational trapping of mismatch recognition complex MSH2/MSH3 on repair-resistant DNA loops.
abstract: Insertion and deletion of small heteroduplex loops are common mutations in DNA, but why some loops are prone to mutation and others are efficiently repaired is unknown. Here we report that the mismatch recognition complex, MSH2/MSH3, discriminates between a repair-competent and a repair-resistant loop by sensing the conformational dynamics of their junctions. MSH2/MSH3 binds, bends, and dissociates from repair-competent loops to signal downstream repair. Repair-resistant Cytosine-Adenine-Guanine (CAG) loops adopt a unique DNA junction that traps nucleotide-bound MSH2/MSH3, and inhibits its dissociation from the DNA. We envision that junction dynamics is an active participant and a conformational regulator of repair signaling, and governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation.
authors.affiliation: Lawrence Berkeley National Laboratory, Life Sciences Division, 1 Cyclotron Road, Berkeley, CA 94720, USA.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Lang
authors.forename: Julie E
authors.initials: JE
authors.lastname: Coats
authors.forename: Jerzy
authors.initials: J
authors.lastname: Majka
authors.forename: Greg L
authors.initials: GL
authors.lastname: Hura
authors.forename: Yuyen
authors.initials: Y
authors.lastname: Lin
authors.forename: Ivan
authors.initials: I
authors.lastname: Rasnik
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D019943:Amino Acid Substitution; D020137:Base Pair Mismatch; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D046912:Multiprotein Complexes; D051718:MutS Homolog 2 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000074081:MutS Homolog 3 Protein; D016297:Mutagenesis, Site-Directed; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; C078444:MSH3 protein, human; D046912:Multiprotein Complexes; D000074081:MutS Homolog 3 Protein; D011994:Recombinant Proteins; D004247:DNA; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein