title: Mlh2 is an accessory factor for DNA mismatch repair in Saccharomyces cerevisiae.
abstract: In Saccharomyces cerevisiae, the essential mismatch repair (MMR) endonuclease Mlh1-Pms1 forms foci promoted by Msh2-Msh6 or Msh2-Msh3 in response to mispaired bases. Here we analyzed the Mlh1-Mlh2 complex, whose role in MMR has been unclear. Mlh1-Mlh2 formed foci that often colocalized with and had a longer lifetime than Mlh1-Pms1 foci. Mlh1-Mlh2 foci were similar to Mlh1-Pms1 foci: they required mispair recognition by Msh2-Msh6, increased in response to increased mispairs or downstream defects in MMR, and formed after induction of DNA damage by phleomycin but not double-stranded breaks by I-SceI. Mlh1-Mlh2 could be recruited to mispair-containing DNA in vitro by either Msh2-Msh6 or Msh2-Msh3. Deletion of MLH2 caused a synergistic increase in mutation rate in combination with deletion of MSH6 or reduced expression of Pms1. Phylogenetic analysis demonstrated that the S. cerevisiae Mlh2 protein and the mammalian PMS1 protein are homologs. These results support a hypothesis that Mlh1-Mlh2 is a non-essential accessory factor that acts to enhance the activity of Mlh1-Pms1.
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, California, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Campbell
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, California, United States of America; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Hombauer
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, California, United States of America.
authors.forename: Anjana
authors.initials: A
authors.lastname: Srivatsan
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, California, United States of America.
authors.forename: Nikki
authors.initials: N
authors.lastname: Bowen
authors.affiliation: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gries
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, California, United States of America; Department of Cellular and Molecular Medicine, University of California School of Medicine, San Diego, La Jolla, California, United States of America; Moores-UCSD Cancer Center, University of California School of Medicine, San Diego, La Jolla, California, United States of America.
authors.forename: Arshad
authors.initials: A
authors.lastname: Desai
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, California, United States of America; Department of Medicine, University of California School of Medicine, San Diego, La Jolla, California, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Putnam
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego, La Jolla, California, United States of America; Department of Cellular and Molecular Medicine, University of California School of Medicine, San Diego, La Jolla, California, United States of America; Moores-UCSD Cancer Center, University of California School of Medicine, San Diego, La Jolla, California, United States of America; Department of Medicine, University of California School of Medicine, San Diego, La Jolla, California, United States of America.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
mesh_terms: D020137:Base Pair Mismatch; D002352:Carrier Proteins / Q000502:physiology; D004249:DNA Damage; D004271:DNA, Fungal / Q000235:genetics*; D016368:Frameshift Mutation; D000070956:MutL Proteins; D009687:Nuclear Proteins / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D004271:DNA, Fungal; C497822:MLH2 protein, S cerevisiae; D009687:Nuclear Proteins; C088858:PMS1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000070956:MutL Proteins