Dataset Information

Studies on Copper and A?1-16-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence.

ABSTRACT: DNA conformation and stability are critical for the normal cell functions, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. The accumulation of amyloid-? peptide (A?) and Copper (Cu) are the etiological factors for neurodegenerative diseases and hypothesized that they can cause DNA instability. In the current investigation, we studied copper and A?1-16 induced conformation and stability changes in CAG/CTG sequences and found alterations from B-DNA to altered B-conformation. Further, the interaction of the copper and A?1-16 with CAG/CTG sequences was studied by molecular docking modeling and results indicated that the interaction of copper and A?1-16 was through the hydrogen bond formation between adenine, guanine, and cytocine. This study illustrates the role of the copper and A?1-16 in modulating the DNA conformation and stability.

SUBMITTER: Govindaraju M

PROVIDER: S-EPMC6159631 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Studies on Copper and Aβ<sub>1-16</sub>-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence.

Govindaraju M M Rao Jayanth K S KS Jagadeesh Kumar D D Prasada Rao U J S UJS Sambasiva Rao K R S KRS Rao K S KS

Journal of Alzheimer's disease reports 20171229 1

DNA conformation and stability are critical for the normal cell functions, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. The accumulation of amyloid-β peptide (Aβ) and Copper (Cu) are the etiological factors for neurodegenerative diseases and hypothesized that they can cause DNA instability. In the current investigation, we studied copper and Aβ<sub>1-16</sub> induced conformation and stability changes in CAG/CTG sequences and found alteratio ...[more]

PMID: 30480244

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Project description:More than 30 human disorders are caused by the expansion of simple sequence DNA repeats, among which triplet repeats remain the most frequent. Most trinucleotide repeat expansion disorders affect primarily the nervous system, through mechanisms of neurodysfunction and/or neurodegeneration. While trinucleotide repeat tracts are short and stably transmitted in unaffected individuals, disease-associated expansions are highly dynamic in the germline and in somatic cells, with a tendency toward further expansion. Since longer repeats are associated with increasing disease severity and earlier onset of symptoms, intergenerational repeat size gains account for the phenomenon of anticipation. In turn, higher levels of age-dependent somatic expansion have been linked with increased disease severity and earlier age of onset, implicating somatic instability in the onset and progression of disease symptoms. Hence, tackling the root cause of symptoms through the control of repeat dynamics may provide therapeutic modulation of clinical manifestations. DNA repair pathways have been firmly implicated in the molecular mechanism of repeat length mutation. The demonstration that repeat expansion depends on functional DNA mismatch repair (MMR) proteins, points to MMR as a potential therapeutic target. Similarly, a role of DNA base excision repair (BER) in repeat expansion has also been suggested, particularly during the removal of oxidative lesions. Using a well-characterized mouse cell model system of an unstable CAG•CTG trinucleotide repeat, we tested if expanded repeat tracts can be stabilized by small molecules with reported roles in both pathways: cadmium (an inhibitor of MMR activity) and a variety of antioxidants (capable of neutralizing oxidative species). We found that chronic exposure to sublethal doses of cadmium and antioxidants did not result in significant reduction of the rate of trinucleotide repeat expansion. Surprisingly, manganese yielded a significant stabilization of the triplet repeat tract. We conclude that treatment with cadmium and antioxidants, at doses that do not interfere with cell survival and cell culture dynamics, is not sufficient to modify trinucleotide repeat dynamics in cell culture.

Dataset Information

Studies on Copper and A?1-16-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence.

Publications

Studies on Copper and Aβ<sub>1-16</sub>-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence.

Similar Datasets

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