Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36.
Demeshkina, Natalia A
Ferré-D'Amaré, Adrian R
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Chen, M. C., Tippana, R., Demeshkina, N. A., Murat, P., Balasubramanian, S., Myong, S., & Ferré-D'Amaré, A. R. (2018). Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36.. Nature, 558 (7710), 465-469. https://doi.org/10.1038/s41586-018-0209-9
Guanine-rich nucleic acid sequences challenge the replication, transcription, and translation machinery by spontaneously folding into G-quadruplexes, the unfolding of which requires forces greater than what most polymerases can exert1,2. Eukaryotic cells host numerous helicases capable of unfolding G-quadruplexes3. The molecular basis for helicase recognition and unfolding of G-quadruplexes remains poorly understood. DHX36 (RHAU, G4R1), a member of the DEAH/RHA family of helicases, binds both DNA and RNA G-quadruplexes with uniquely high affinity4,5,6, is consistently found bound to G-quadruplexes in cells7,8, and is a major source of G-quadruplex unfolding activity in HeLa cell lysates6. DHX36 is a multi-functional helicase implicated in G-quadruplex-mediated transcriptional and post-transcriptional regulation, and is essential for heart development, hematopoiesis, and embryogenesis in mice9,10,11,12. Here, we report the co-crystal structure of bovine DHX36 bound to a DNA with a G-quadruplex and a 3' single-stranded (ssDNA) segment. We show that the N-terminal DHX36-specific motif folds into a DNA-binding-induced -helix that together with the OB-fold-like subdomain selectively binds parallel G-quadruplexes. Comparison with our unliganded and ATP-analog-bound DHX36 structures, together with single-molecule FRET analysis, suggests that G-quadruplex binding alone induces rearrangements of the helicase core, which by pulling on its ssDNA tail, drive G-quadruplex unfolding by one residue at a time.
Animals, Cattle, DNA, Crystallography, X-Ray, Fluorescence Resonance Energy Transfer, Amino Acid Motifs, Nucleic Acid Denaturation, Mutation, Models, Molecular, DEAD-box RNA Helicases, G-Quadruplexes
Cancer Research UK (18618)
Wellcome Trust (099232/Z/12/Z)
European Research Council (339778)
External DOI: https://doi.org/10.1038/s41586-018-0209-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278626