Nucleosome remodeling by hMSH2-hMSH6.
DNA nucleotide mismatches and lesions arise on chromosomes that are a complex assortment of protein and DNA (chromatin). The fundamental unit of chromatin is a nucleosome that contains approximately 146 bp DNA wrapped around an H2A, H2B, H3, and H4 histone octamer. We demonstrate that the mismatch recognition heterodimer hMSH2-hMSH6 disassembles a nucleosome. Disassembly requires a mismatch that provokes the formation of hMSH2-hMSH6 hydrolysis-independent sliding clamps, which translocate along the DNA to the nucleosome. The rate of disassembly is enhanced by actual or mimicked acetylation of histone H3 within the nucleosome entry-exit and dyad axis that occurs during replication and repair in vivo and reduces DNA-octamer affinity in vitro. Our results support a passive mechanism for chromatin remodeling whereby hMSH2-hMSH6 sliding clamps trap localized fluctuations in nucleosome positioning and/or wrapping that ultimately leads to disassembly, and highlight unanticipated strengths of the Molecular Switch Model for mismatch repair (MMR).
Javaid
Sarah
S
Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics, The Ohio State University and The Ohio State University Medical Center, Columbus, 43210, USA.
Manohar
Mridula
M
Punja
Nidhi
N
Mooney
Alex
A
Ottesen
Jennifer J
JJ
Poirier
Michael G
MG
Fishel
Richard
R
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020137:Base Pair Mismatch; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000378:metabolism; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D014982:Xenopus laevis
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D006657:Histones; D009707:Nucleosomes; D000255:Adenosine Triphosphate; D004247:DNA; D000251:Adenosine Triphosphatases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein