Doctoral Studies

Biomolecular Chemistry - Field

Topic name: Environmentally Controlled Polymorphism of non-B-DNA

Supervisor:

Předběžné zadání:
Repetitive blocks of guanine- and (complementary) cytosine-rich sequences have ability to form G- and C-quadruplex (called i-motif) structures. These non-B DNA structures detected in centromeric, telomeric DNA regions and in promoter regions of protein coding proto-oncogenes are involved in more then 40 pathological human conditions including cancer. G-quadruplexes formed in telomeres and the regulatory regions of many genes have become valid targets for new anticancer drugs in the past two decades. Many leading compounds that target these structures have been reported, and a few of them have entered preclinical or clinical trials. Nonetheless, the selectivity of this kind of (mainly) antitumor compound has yet to be improved in order to suppress the side effects caused by nonselective binding. As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles, and the modes and sites of small-ligand binding to these structures needs to be clearly understood. From a biophysical point of view, a property common to both G- and C-rich sequences, which have ability to form the quadruplex structures, is their inherent sensitivity to non-specific, physical-chemical environmental factors promoting theirs conformational polymorphism. In vitro studies have shown that the stability and the folding topology of both the G-quadruplexes and the i-motifs strongly depend on the activity of water in the environment, molecular crowding, pH, and/or nature of the counter ions Despite significant effort motivated by both biological significance and biotechnological and biomedical applications of these quadruplex structures, the mechanistic nature of these environmentally induced effects remains poorly understood. The mechanistic insight and revealing of relationships between the DNA sequence and its folding topology in relation to its environment is essential for both rational design of novel nano-materials and ways for their manipulations. The mechanistic insight is also crucial for potential biomedical applications. If we can control the non-B-DNA structures in cells, effective therapeutic strategies might be considered for many of the related diseases. AIMS of the proposed project: 1] Characterization of the folding topologies and conformational polymorphism of the G- and C-rich DNA sequences under native-like conditions. 2] Identification of environmental factors modulating structure and conformational equilibrium of non-B DNA in relation to its sequence.
Poznámka:
vedoucí:Mgr. Lukáš Trantírek, Ph.D. učo 8725


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