Effect of oxidative stress on human telomeric DNA structural dynamics and accessibility

Oxidative stress;8-oxo-guanine;Quadruplex;Deoxyribonucleic Acid (DNA);Telomere;Accessibility

Kim, Grace ; Myong ; Su-A

关键词: Oxidative stress;    8-oxo-guanine;    Quadruplex;    Deoxyribonucleic Acid (DNA);    Telomere;    Accessibility;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/73080/Grace_Kim.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The ends of human telomeric DNA consist of single-stranded overhangs of tandem TTAGGG repeats (ssTEL) that can form into a G-quadruplex (GQ). This guanine-rich sequence is prone to 8-oxoguanine (8OG) damage, which is one of the most common oxidative DNA lesions that can compromise telomere integrity. Here, we use single molecule Förster Resonance Energy Transfer (smFRET) to characterize the effect of 8OG on the structural dynamics and accessibility of ssTEL. We show that the stable GQ folding observed in ssTEL is disrupted by a single 8OG, generating dynamic conformational fluctuations of the DNA. Such structural dynamics induced by 8OG contributes to increased passive binding of complementary DNA oligonucleotides, as well as faster and more effective active binding of the protection of telomeres 1 (POT1) shelterin protein, suggesting enhanced accessibility of telomeric DNA to interacting molecules. The increased dynamics and accessibility caused by 8OG is comparable to the effect of a base substitution from G to C at the same position, which abolishes the Hoogsteen basepairing required for GQ folding. Our results suggest that a single 8OG can lead to destabilization of GQ folding, which may allow loading of telomeric proteins, including those involved in telomere length maintenance.