Integrative Computational Analysis of Common EXO5 Haplotypes: Impact on Protein Dynamics, Genome Stability, and Cancer Progression

Understanding the
impact of common germline variants on protein
structure, function, and disease progression is crucial in cancer
research. This study presents a comprehensive analysis of the EXO5 gene, which encodes a DNA exonuclease involved in DNA
repair that was previously associated with cancer susceptibility.
We employed an integrated approach combining genomic and clinical
data analysis, deep learning variant effect prediction, and molecular
dynamics (MD) simulations to investigate the effects of common EXO5 haplotypes on protein structure, dynamics, and cancer
outcomes. We characterized the haplotype structure of EXO5 across diverse human populations, identifying five common haplotypes,
and studied their impact on the EXO5 protein. Extensive, all-atom
MD simulations revealed significant structural and dynamic differences
among the EXO5 protein variants, particularly in their catalytic region.
The L151P EXO5 protein variant exhibited the most substantial conformational
changes, potentially disruptive for EXO5′s function and nuclear
localization. Analysis of The Cancer Genome Atlas data showed that
cancer patients carrying L151P EXO5 had significantly shorter progression-free
survival in prostate and pancreatic cancers and exhibited increased
genomic instability. This study highlights the strength of our methodology
in uncovering the effects of common genetic variants on protein function
and their implications for disease outcomes.