Molecular Properties of Telomeric TRF1/TRF2 - DNA Systems

Abstract

Telomeres are nucleoprotein complexes that protect the ends of linear eukaryotic chromosomes from degradation and fusion. Human telomeric DNA contains tandem arrays of double stranded TTAGGG repeats. Telomeric DNA forms specific complexes with many different proteins (shelterins), among which TRF1 and TRF2 are the most essential for the maintenance of telomere structure and function. TRF1 is a negative regulator of telomere length whereas TRF2 is involved in formation of telomeric higher order structures (t-loops), and functions more related to capping the DNA end. Both proteins bind to DNA as pre-formed homodimers. Although cellular functions of both these proteins are different, their structures are very similar. Both TRF1 and TRF2 contain two conserved sequence motives which form specific domains, namely homodimerisation and Myb-DNA binding domains.In order to reveal the molecular properties of both proteins and also differences between binding modes of TRF1 and TRF2 to telomeric DNA, detailed studies of both binding domains have been performed. We carried out molecular dynamic simulations of TRF1 and TRF2 binding domains and their complexes with DNA. Starting models of studied systems were based on X-ray structures of TRF1 and TRF2 Myb-DNA binding domains [1]. The results have revealed structural differences between bound proteins and structural differences of their binding patterns with DNA. Additionally, we provide experimental evidence that interaction of both shelterins and DNA can be specifically perturbed by small molecular weight ligands. These results support the idea that TRF1/TRF2 - DNA systems are potential new targets for anticancer therapy.1. R. Court, L. Chapman, L. Fairall, D. Rhodes, EMBO Reports 6 (2005) 39-45.