title: Msh2-Msh3 interferes with Okazaki fragment processing to promote trinucleotide repeat expansions.
abstract: Trinucleotide repeat (TNR) expansions are the underlying cause of more than 40 neurodegenerative and neuromuscular diseases, including myotonic dystrophy and Huntington's disease. Although genetic evidence points to errors in DNA replication and/or repair as the cause of these diseases, clear molecular mechanisms have not been described. Here, we focused on the role of the mismatch repair complex Msh2-Msh3 in promoting TNR expansions. We demonstrate that Msh2-Msh3 promotes CTG and CAG repeat expansions in vivo in Saccharomyces cerevisiae. Furthermore, we provide biochemical evidence that Msh2-Msh3 directly interferes with normal Okazaki fragment processing by flap endonuclease1 (Rad27) and DNA ligase I (Cdc9) in the presence of TNR sequences, thereby producing small, incremental expansion events. We believe that this is the first mechanistic evidence showing the interplay of replication and repair proteins in the expansion of sequences during lagging-strand DNA replication.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
authors.forename: Athena
authors.initials: A
authors.lastname: Kantartzis
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Williams
authors.forename: Lata
authors.initials: L
authors.lastname: Balakrishnan
authors.forename: Rick L
authors.initials: RL
authors.lastname: Roberts
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Surtees
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bambara
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D000074081:MutS Homolog 3 Protein; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: C000607890:CDC9 protein, S cerevisiae; D004268:DNA-Binding Proteins; C000607892:LIG1 protein, human; C081696:MSH3 protein, S cerevisiae; D000074081:MutS Homolog 3 Protein; C022262:Okazaki fragments; D029701:Saccharomyces cerevisiae Proteins; D004247:DNA; D000251:Adenosine Triphosphatases; C071451:RAD57 protein, S cerevisiae; C489751:MSH2 protein, S cerevisiae; D051718:MutS Homolog 2 Protein; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP