Telomere uncapping by common oxidative guanine lesions: Insights from atomistic models.

Oxidative damage to DNA is widely known to contribute to aging and disease. This relationship has been extensively studied for telomeres - structures that cap chromosome ends - due to their role in cell proliferation and senescence, and exceptional susceptibility to oxidation. Indeed, the repetitive telomeric DNA sequence contains the 5'-GGG-3' motif that has the lowest ionization potential of all trinucleotides. Accordingly, experiments consistently show that telomeric oxidative lesions are more abundant and persistent than elsewhere in the genome. This led to a hypothesis that telomeres act as sensors of prolonged oxidative stress and prevent carcinogenesis, as disruption of telomeric integrity triggers senescence or apoptosis. Here, we use atomistic alchemical Molecular Dynamics simulations to perform a combinatorial assessment of changes in DNA binding affinity of telomeric proteins induced by oxidative guanine lesions. We rank lesions by their effect on telomere integrity, as well as telomeric proteins by their sensitivity to DNA oxidation. While the binding of most proteins is abolished by DNA oxidation, HOT1 emerges as a notable exception, suggesting its potential role in sensing of oxidative damage. Through statistical analysis and free energy decomposition, we also identify common trends in structural responses of protein-DNA complexes that contribute to decreased binding affinity.
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