Studies on copper (II) interaction with the (CCG)12 repeats sequence: An insight into genomic instability in neurodegeneration.

BACKGROUND

Studies indicate that a comprehensive understanding of the mechanisms underlying neurodegeneration in Alzheimer's disease, Parkinson's disease, and related disorders is still not clearly understood. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such late-onset neurodegenerative disorder characterized by premutation alleles (55-200 CGG repeats) in the genome. In parallel, dysregulation of trace metal homeostasis, particularly copper (Cu) imbalance, has been documented in Alzheimer's disease, Parkinson's disease, and FXTAS. However, the precise role of trace metal dyshomeostasis as a disease modifier in neurodegeneration, and its contribution to disease onset and progression, remains poorly understood.

OBJECTIVE

To understand the interaction of Copper (II) with the (CCG)12 repeats sequence using spectroscopic and computational modeling studies.

METHODS

(CCG)12 repeats were done by the phosphonamidite technique with a 380B ABI automated synthesizer. The binding of Cu to (CCG)12 was studied using Circular Dichroism, Fluorescence, UV spectroscopy, and a molecular docking model.

RESULTS

The current study shows conformational changes to the (CCG)12 repeat sequence by abnormal interactions of Cu using CD and other spectroscopic methods. Circular dichroism results confirm binding of Cu to the base pairs of DNAs and alter the structure from B-DNA to an altered B-DNA conformation. Further, molecular docking studies reveal the Cu binding to DNA directly through the hydrogen bond formation between G-C base pairs.

CONCLUSIONS

The altered form of B-DNA will affect the integrity of DNA, which in turn modulates the replication and transcription processes, leading to genomic instability and cell dysfunction in neurodegenerative disorders.