Fanconi anemia complementation group D2 (FANCD2) protein plays pivotal role in DNA interstrand crosslink (ICL) repair and genome stability. FANCD2 comprises conserved CUE domain at N terminus, which is important for DNA ICL repair and protein stability. However, molecular mechanism associated to genetic alteration has not well characterized. Here, we have carried out multimodal approaches to explore folding pattern of FANCD2 Cue domain and functionally relevant mutations. Dynamic Light Scattering and Mass Spectrometry data of purified proteins could revealed that wild- type protein is predominantly monomeric, but mutated counterparts are exhibiting oligomeric properties. Secondary, tertiary structure assessment and their thermal stability of wild- type, mutants were studied by Circular Dichroism (CD) and Fluorescence spectroscopy. Furthermore, binding affinity and kinetics of Cue domain and mutants with monoubiquitin was evaluated by surface plasmon resonance (SPR). Molecular modelling, simulation, normal mode analysis, principal component analysis and docking studies were carried out to understand in-depth conformational dynamics and interactions. References:- 1. Regulation of the Fanconi anemia pathway by a CUE ubiquitin-binding domain in the FANCD2 protein. Rego, M. A. et al, Blood 120: 2109-2117,(2012). 2. Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. Kalb et al, Am J Hum Genet 80: 895-910, (2007)

Citation Format: Mohd Quadir Siddiqui, Ashok K. Varma. Structural evaluation of mutations identified on Cue domain of FANCD2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4546. doi:10.1158/1538-7445.AM2017-4546