title: Structural and functional divergence of MutS2 from bacterial MutS1 and eukaryotic MSH4-MSH5 homologs.
abstract: MutS homologs, identified in nearly all bacteria and eukaryotes, include the bacterial proteins MutS1 and MutS2 and the eukaryotic MutS homologs 1 to 7, and they often are involved in recognition and repair of mismatched bases and small insertion/deletions, thereby limiting illegitimate recombination and spontaneous mutation. To explore the relationship of MutS2 to other MutS homologs, we examined conserved protein domains. Fundamental differences in structure between MutS2 and other MutS homologs suggest that MutS1 and MutS2 diverged early during evolution, with all eukaryotic homologs arising from a MutS1 ancestor. Data from MutS1 crystal structures, biochemical results from MutS2 analyses, and our phylogenetic studies suggest that MutS2 has functions distinct from other members of the MutS family. A mutS2 mutant was constructed in Helicobacter pylori, which lacks mutS1 and mismatch repair genes mutL and mutH. We show that MutS2 plays no role in mismatch or recombinational repair or deletion between direct DNA repeats. In contrast, MutS2 plays a significant role in limiting intergenomic recombination across a range of donor DNA tested. This phenotypic analysis is consistent with the phylogenetic and biochemical data suggesting that MutS1 and MutS2 have divergent functions.
authors.affiliation: Department of Microbiology, New York University School of Medicine, and VA Medical Center, New York, NY 10016, USA. kangm01@med.nyu.edu
authors.forename: Josephine
authors.initials: J
authors.lastname: Kang
authors.forename: Shuyan
authors.initials: S
authors.lastname: Huang
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Blaser
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics*; D018797:Cell Cycle Proteins; D017124:Conserved Sequence; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D019143:Evolution, Molecular; D017353:Gene Deletion; D016480:Helicobacter pylori / Q000235:genetics*; D008969:Molecular Sequence Data; D051719:MutS DNA Mismatch-Binding Protein; D051718:MutS Homolog 2 Protein; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D020079:Terminal Repeat Sequences / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C409221:MSH4 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D000251:Adenosine Triphosphatases; D051719:MutS DNA Mismatch-Binding Protein; D051718:MutS Homolog 2 Protein