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dc.contributor.authorChen, Michael Cen
dc.contributor.authorMurat, Pierreen
dc.contributor.authorAbecassis, Kerenen
dc.contributor.authorFerré-D’Amaré, Adrian Ren
dc.contributor.authorBalasubramanian, Shankaren
dc.date.accessioned2015-03-31T14:04:56Z
dc.date.available2015-03-31T14:04:56Z
dc.date.issued2015-02-04en
dc.identifier.citationNucleic Acids Research, 2015, Vol. 43, No. 4 2223–2231, doi: 10.1093/nar/gkv051en
dc.identifier.issn0305-1048
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247234
dc.description.abstractThe unwinding of nucleic acid secondary structures within cells is crucial to maintain genomic integrity and prevent abortive transcription and translation initiation. DHX36, also known as RHAU or G4R1, is a DEAH-box ATP-dependent helicase highly specific for DNA and RNA G-quadruplexes (G4s). A fundamental mechanistic understanding of the interaction between helicases and their G4 substrates is important to elucidate G4 biology and pave the way toward G4-targeted therapies. Here we analyze how the thermodynamic stability of G4 substrates affects binding and unwinding by DHX36. We modulated the stability of the G4 substrates by varying the sequence and the number of G-tetrads and by using small, G4-stabilizing molecules. We found an inverse correlation between the thermodynamic stability of the G4 substrates and rates of unwinding by DHX36. In stark contrast, the ATPase activity of the helicase was largely independent of substrate stability pointing toward a decoupling mechanism akin to what has been observed for many double-stranded DEAD-box RNA helicases. Our study provides the first evidence that DHX36 uses a local, non-processive mechanism to unwind G4 substrates, reminiscent of that of eukaryotic initiation factor 4A (eIF4A) on double-stranded substrates.
dc.description.sponsorshipCancer Research UK and ERC (Balasubramanian group); Cambridge Trust studentship (to M.C.C.); Intramural Program of the National Heart, Lung and Blood Institute, NIH; ALS on the Berkeley Center for Structural Biology beamlines, US National Institutes of Health (NIH); NIH Oxford Cambridge Scholars Program [to M.C.C.]. Funding for open access charge: University of Cambridge.
dc.languageEnglishen
dc.language.isoenen
dc.publisherOUP
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.titleInsights into the mechanism of a G-quadruplex-unwinding DEAH-box helicaseen
dc.typeArticle
dc.description.versionThis is the final published version. The article was originally published in Nucleic Acids Research, 2015, Vol. 43, No. 4 2223–2231, doi: 10.1093/nar/gkv051.en
prism.endingPage2231
prism.publicationDate2015en
prism.startingPage2223
prism.volume43en
dc.rioxxterms.funderCRUK
rioxxterms.versionofrecord10.1093/nar/gkv051en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-02-04en
dc.contributor.orcidBalasubramanian, Shankar [0000-0002-0281-5815]
dc.identifier.eissn1362-4962
rioxxterms.typeJournal Article/Reviewen


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales