Crystal structure of parallel quadruplexes from human telomeric DNA

Abstract

Telomeric ends of chromosomes, which comprise noncoding repeat sequences of guanine-rich DNA, are fundamental in protecting the cell from recombination and degradation¹. Disruption of telomere maintenance leads to eventual cell death, which can be exploited for therapeutic intervention in cancer. Telomeric DNA sequences can form four-stranded (quadruplex) structures^2,3,4, which may be involved in the structure of telomere ends⁵. Here we describe the crystal structure of a quadruplex formed from four consecutive human telomeric DNA repeats and grown at a K⁺ concentration that approximates its intracellular concentration. K⁺ ions are observed in the structure. The folding and appearance of the DNA in this intramolecular quadruplex is fundamentally different from the published Na⁺-containing quadruplex structures^2,4,6. All four DNA strands are parallel, with the three linking trinucleotide loops positioned on the exterior of the quadruplex core, in a propeller-like arrangement. The adenine in each TTA linking trinucleotide loop is swung back so that it intercalates between the two thymines. This DNA structure suggests a straightforward path for telomere folding and unfolding, as well as ways in which it can recognize telomere-associated proteins.