title: Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair.
abstract: The human mismatch repair (MMR) proteins hMLH1 and hPMS2 function in MMR as a heterodimer. Cells lacking either protein have a strong mutator phenotype and display microsatellite instability, yet mutations in the hMLH1 gene account for approximately 50% of hereditary nonpolyposis colon cancer families, whereas hPMS2 mutations are substantially less frequent and less penetrant. Similarly, in the mouse model, Mlh1-/- animals are highly cancer prone and present with gastrointestinal tumors at an early age, whereas Pms2-/- mice succumb to cancer much later in life and do not present with gastrointestinal tumors. This evidence suggested that MLH1 might functionally interact with another MutL homologue, which compensates, at least in part, for a deficiency in PMS2. Sterility of Mlh1-/-, Pms2-/-, and Mlh3-/- mice implicated the Mlh1/Pms2 and Mlh1/Mlh3 heterodimers in meiotic recombination. We now show that the hMLH1/hMLH3 heterodimer, hMutLgamma, can also assist in the repair of base-base mismatches and single extrahelical nucleotides in vitro. Analysis of hMLH3 expression in colon cancer cell lines indicated that the protein levels vary substantially and independently of hMLH1. If hMLH3 participates in MMR in vivo, its partial redundancy with hPMS2, coupled with the fluctuating expression levels of hMLH3, may help explain the low penetrance of hPMS2 mutations in hereditary nonpolyposis colon cancer families.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: Elda
authors.initials: E
authors.lastname: Cannavo
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.forename: Jacob
authors.initials: J
authors.lastname: Sabates-Bellver
authors.forename: Mirco
authors.initials: M
authors.lastname: Menigatti
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.forename: Franziska
authors.initials: F
authors.lastname: Fischer
authors.forename: Petr
authors.initials: P
authors.lastname: Cejka
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D020137:Base Pair Mismatch; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000502:physiology*; D006801:Humans; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018411:Spodoptera / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; C403623:MLH3 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins