Oncogenic Mutations in the DNA-Binding Domain of FOXO1 that Disrupt Folding: Quantitative Insights from Experiments and Molecular Simulations.

ABSTRACT: FOXO1, a member of the family of winged-helix motif Forkhead box (FOX) transcription factors, is the most abundantly expressed FOXO member in mature B cells. Sequencing of diffuse large B-cell lymphoma (DLBCL) tumors and cell lines identified specific mutations in the forkhead domain linked to loss of function. Differential scanning calorimetry and thermal shift assays were used to characterize how eight of these mutations affect the stability of the FOX domain. Mutations L183P and L183R were found to be particularly destabilizing. Electrophoresis mobility shift assays show these same mutations also disrupt FOXO1 binding to their canonical DNA sequences, suggesting that the loss of function is due to destabilization of the folded structure. Computational modeling of the effect of mutations

SUBMITTER: Novack D 

PROVIDER: S-EPMC9482095 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature