Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36

Michael C. Chen, Ramreddy Tippana, Natalia A. Demeshkina, Pierre Murat, Shankar Balasubramanian, Sua Myong and Adrian R. Ferré-D’Amaré ()
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Michael C. Chen: National Heart, Lung and Blood Institute
Ramreddy Tippana: Johns Hopkins University
Natalia A. Demeshkina: National Heart, Lung and Blood Institute
Pierre Murat: University of Cambridge
Shankar Balasubramanian: University of Cambridge
Sua Myong: Johns Hopkins University
Adrian R. Ferré-D’Amaré: National Heart, Lung and Blood Institute

Nature, 2018, vol. 558, issue 7710, 465-469

Abstract: Abstract 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 most polymerases can exert1,2. Eukaryotic cells contain numerous helicases that can unfold G-quadruplexes 3 . The molecular basis of the recognition and unfolding of G-quadruplexes by helicases remains poorly understood. DHX36 (also known as RHAU and G4R1), a member of the DEAH/RHA family of helicases, binds both DNA and RNA G-quadruplexes with extremely high affinity4–6, is consistently found bound to G-quadruplexes in cells7,8, and is a major source of G-quadruplex unfolding activity in HeLa cell lysates 6 . DHX36 is a multi-functional helicase that has been implicated in G-quadruplex-mediated transcriptional and post-transcriptional regulation, and is essential for heart development, haematopoiesis, and embryogenesis in mice9–12. Here we report the co-crystal structure of bovine DHX36 bound to a DNA with a G-quadruplex and a 3′ single-stranded DNA segment. We show that the N-terminal DHX36-specific motif folds into a DNA-binding-induced α-helix that, together with the OB-fold-like subdomain, selectively binds parallel G-quadruplexes. Comparison with unliganded and ATP-analogue-bound DHX36 structures, together with single-molecule fluorescence resonance energy transfer (FRET) analysis, suggests that G-quadruplex binding alone induces rearrangements of the helicase core; by pulling on the single-stranded DNA tail, these rearrangements drive G-quadruplex unfolding one residue at a time.

Date: 2018
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DOI: 10.1038/s41586-018-0209-9

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