title: Functional and physical interaction between the mismatch repair and FA-BRCA pathways.
abstract: Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and an increased risk for leukemia and cancer. Fifteen proteins thought to function in the repair of DNA interstrand crosslinks (ICLs) comprise what is known as the FA-BRCA pathway. Activation of this pathway leads to the monoubiquitylation and chromatin localization of FANCD2 and FANCI. It has previously been shown that FANCJ interacts with the mismatch repair (MMR) complex MutLα. Here we show that FANCD2 interacts with the MMR proteins MSH2 and MLH1. FANCD2 monoubiquitylation, foci formation and chromatin loading are greatly diminished in MSH2-deficient cells. Human or mouse cells lacking MSH2 or MLH1 display increased sensitivity and radial formation in response to treatment with DNA crosslinking agents. Studies in human cell lines and Drosophila mutants suggest an epistatic relationship between FANCD2, MSH2 and MLH1 with regard to ICL repair. Surprisingly, the interaction between MSH2 and MLH1 is compromised in multiple FA cell lines, and FA cell lines exhibit deficient MMR. These results suggest a significant role for MMR proteins in the activation of the FA pathway and repair of ICLs. In addition, we provide the first evidence for a defect in MMR in FA cell lines.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Williams
authors.forename: James B
authors.initials: JB
authors.lastname: Wilson
authors.forename: Allison P
authors.initials: AP
authors.lastname: Clark
authors.forename: Alyssa
authors.initials: A
authors.lastname: Mitson-Salazar
authors.forename: Andrei
authors.initials: A
authors.lastname: Tomashevski
authors.forename: Sahana
authors.initials: S
authors.lastname: Ananth
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
authors.forename: O John
authors.initials: OJ
authors.lastname: Semmes
authors.forename: Allen E
authors.initials: AE
authors.lastname: Bale
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Jones
authors.forename: Gary M
authors.initials: GM
authors.lastname: Kupfer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D053843:DNA Mismatch Repair / Q000502:physiology*; D004330:Drosophila; D005199:Fanconi Anemia / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C519921:FANCI protein, human; D051856:Fanconi Anemia Complementation Group Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein