Journal
NATURE
Volume 558, Issue 7710, Pages 465-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-018-0209-9
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Funding
- US National Insitutes of Health (NIH)
- US Department of Energy
- NIH [GM105453]
- American Chemical Society [RSG-12-066-01-DMC]
- National Science Foundation Physics Frontiers Center Program [0822613]
- Wellcome Trust [099232/z/12/z]
- European Research Council [339778]
- Cancer Research UK [C12303/A17197, C9681/A18618]
- NIH-Oxford-Cambridge Scholars Program
- Cambridge Trust
- intramural program of the NHLBI, NIH
- Division Of Physics
- Direct For Mathematical & Physical Scien [0822613] Funding Source: National Science Foundation
- European Research Council (ERC) [339778] Funding Source: European Research Council (ERC)
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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 exert(1,2). 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 affinity(4-6), is consistently found bound to G-quadruplexes in 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 mice(9-12). 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 alpha-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.
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