School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032 India.
J Phys Chem B. 2024 Jul 25;128(29):7121-7128. doi: 10.1021/acs.jpcb.4c02969. Epub 2024 Jul 15.
The stability of the human telomere G-quadruplex (G4) is directly linked to cancer disease. The human telomere is mostly associated with the flanking nucleobases, which can affect the stability of G4. Hence, in this study, the effect of the flanking nucleobases in the context of their chemical nature, number, and position on the structure and stability of G4 has been investigated in varying concentrations of KCl mimicking the normal and cancer KCl microenvironments. The addition of flanking nucleobases does not alter the G4 topology. However, the presence of merely a single flanking nucleobase destabilizes the telomeric G4. This destabilizing effect is more prominent for thymine than adenine flanking nucleobase, probably due to the formation of the intermolecular G4 topology by thymine. Interestingly, the change in the stability of the telomeric G4 in the presence of thymine flanking nucleobase is sensitive to the concentration of KCl relevant to the normal and cancerous microenvironments, in contrast to adenine. Flanking nucleobases have a greater impact at the 5' end compared to the 3' end, particularly noticeable in KCl concentrations resembling the normal microenvironment rather than the cancerous one. These findings indicate that the effect of the flanking nucleobases on telomeric G4 is different in the KCl salt relevant to normal and cancerous microenvironments. This study may be helpful in attaining molecular-level insight into the role of G4 in telomeric length regulation under normal and cancerous KCl salt conditions.
人类端粒 G-四链体 (G4) 的稳定性与癌症直接相关。人类端粒主要与侧翼核碱基相关，这些核碱基可以影响 G4 的稳定性。因此，在这项研究中，在模拟正常和癌症 KCl 微环境的不同 KCl 浓度下，研究了侧翼核碱基的化学性质、数量和位置对 G4 结构和稳定性的影响。侧翼核碱基的添加不会改变 G4 的拓扑结构。然而，仅仅存在一个侧翼核碱基就会使端粒 G4 不稳定。这种去稳定效应对于胸腺嘧啶比对腺嘌呤侧翼核碱基更为明显，可能是由于胸腺嘧啶形成了分子间 G4 拓扑结构。有趣的是，在存在胸腺嘧啶侧翼核碱基的情况下，端粒 G4 的稳定性变化对与正常和癌变微环境相关的 KCl 浓度敏感，而与腺嘌呤不同。侧翼核碱基在 5'端的影响大于 3'端，尤其是在类似于正常微环境而非癌变微环境的 KCl 浓度下更为明显。这些发现表明，侧翼核碱基对端粒 G4 的影响在与正常和癌变微环境相关的 KCl 盐中是不同的。这项研究可能有助于在正常和癌变 KCl 盐条件下获得关于 G4 在端粒长度调节中作用的分子水平的见解。
