title: The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair.
abstract: Loss of the DNA mismatch repair (MMR) protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSβ (MSH2-MSH3) complex in late-onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3(-/-) mice onto a tumor predisposing p53-deficient background. Survival of Msh3/p53 mice was not reduced compared with p53 single mutant mice; however, the tumor spectrum changed significantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis. Interestingly, Msh3(-/-) mouse embryonic fibroblasts displayed increased chromatid breaks and persistence of γH2AX foci following ionizing radiation, indicating a defect in DNA double-strand break repair (DSBR). Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy-number variation and a moderate microsatellite instability phenotype compared with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability. Our results show that the MSH2-MSH3 complex is important for the suppression of late-onset tumors due to its roles in DNA DSBR as well as in DNA MMR. Further, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis and possibly has a role in other chromosomally unstable tumors as well.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J M M
authors.initials: JM
authors.lastname: van Oers
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Edwards
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chahwan
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Pechuan
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Schaetzlein
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Jin
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bergman
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Scharff
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Edelmann
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002478:Cells, Cultured; D043171:Chromosomal Instability; D053903:DNA Breaks, Double-Stranded; D056915:DNA Copy Number Variations; D053843:DNA Mismatch Repair; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074081:MutS Homolog 3 Protein; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C089762:Msh3 protein, mouse; D000074081:MutS Homolog 3 Protein; D011506:Proteins; D016159:Tumor Suppressor Protein p53