2013年伊始，六十年前发现DNA双螺旋结构的剑桥科学家又证实人类基因组中G-四链螺旋结构确实会在细胞中形成，可能拥有人们先前无法想象的重要生物学功能。细胞中四链螺旋结构受到一种高度特异专一的四链螺旋解旋酶的调控，其功能直接影响基因表达，端粒代谢和维护基因组稳定性。我们拟以两种具有代表性的DNA和RNA四链螺旋解旋酶Werner和RHAU蛋白为研究对象，整合发展传统的系综方法和单分子荧光操纵以及X光衍射结构生物学多学科交叉技术手段，深入研究四链螺旋解旋酶特有的物化性质，探索四链螺旋解旋酶如何识别和解开四链螺旋的分子机理以及如何同其他生物大分子有机协调共同作用，完成端粒代谢、调控染色体组稳定性等复杂的生物学功能。通过阐明四链螺旋解旋酶的三维结构揭示其作用机理的结构生物学基础。本计划的实施，对于理解四链螺旋解旋酶的分子作用机理，推动基础生物学的发展，提供延缓人类衰老和肿瘤治疗新策略有重要意义。

At the beginning of 2013, the researchers at Cambridge where the scientists discovered the DNA double helix structure sixty years ago，confirmed that the G-quadruplex structure in the human genome does form in cells, indicating that the G-quadruplex may have important biological functions previously unimaginable. In cell, unwinding of G-quadruplex is highly regulated by a special family of helicases, its functionality directly affect gene expression, telomere metabolism and maintenance of genomic stability. We intend to study two representative DNA and RNA G-quadruplex helicases: the Werner and RHAU proteins. By integrating and developing the traditional ensemble methods, single-molecule fluorescence manipulation and structural biology, as well as other multidisciplinary technical means, we will depthly study physical and chemical properties of helicases that mediated the unwinding of G-quadruplex, and further explore the molecular mechanisms underlying the recognition and unwinding of G-quadruplex, understand how the G-quadruplex helicases act coordinately with other biological macromolecules to perform the complex biological functions in telomere metabolism and regulation of genome stability. By revealing their three dimensional structure, we elucidate the structural basis of the mechanism of action of G-quadruplex helicases. Achieving the proposal goals, will be important to understand the molecular mechanism of G-quadruplex helicase, promote the development of the basic biology and provide important new strategy to delay human aging and cancer therapy.