Investigating the effects of the ARG258HIS mutation on RAD51C in inherited Fanconi Anemia and cancer disease

Fanconi anemia is a rare chromosomal instability disorder associated with developmental abnormalities, bone marrow failure, and a heightened susceptibility to leukemia and other cancers. It is an autosomal recessive genetic disorder, necessitating both parents to carry the faulty gene. Diagnostic methods include blood tests, chromosome breakage assessments, and genetic testing. While there is no cure, treatments encompass blood transfusions, bone marrow transplants, and gene therapy, with patients requiring regular check-ups, supportive care, and cancer screening to enhance their quality of life. In this study, we identify a specific substitution (R258H) targeting the crucial binding site of the alpha-helix region in RAD51C. This substitution induces structural disorder in distinct regions, as indicated by the near absence of electron density for multiple amino acids. Intriguingly, these disordered regions do not follow a continuous sequence from the mutation site and extend across domain boundaries. We utilized computational prediction algorithms and Molecular Dynamics (MD) simulations to model RAD51C and its mutation (R258H) structurally. These simulations highlighted alterations in conformational dynamics, the Free Energy Landscape (FEL), and intrinsic molecular motions induced by the mutation, suggesting structural destabilization that could disrupt its function. This observed destabilization in RAD51C due to mutations offers valuable insights that may serve as diagnostic markers for individuals carrying these mutations, particularly in Fanconi anemia.