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

被引:242
作者
Chen, Michael C. [1 ,2 ]
Tippana, Ramreddy [3 ]
Demeshkina, Natalia A. [1 ]
Murat, Pierre [2 ]
Balasubramanian, Shankar [2 ,4 ]
Myong, Sua [3 ]
Ferre-D'Amare, Adrian R. [1 ]
机构
[1] NHLBI, Biochem & Biophys Ctr, Bldg 10, Bethesda, MD 20892 USA
[2] Univ Cambridge, Dept Chem, Cambridge, England
[3] Johns Hopkins Univ, Biophys Dept, Baltimore, MD USA
[4] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England
基金
欧洲研究理事会; 美国国家科学基金会; 英国惠康基金;
关键词
TETRAMOLECULAR QUADRUPLEX; RESOLVING ACTIVITY; MAJOR SOURCE; RNA; RHAU; BINDS; UNWINDS; DNA; TRANSLOCATION; RECOGNITION;
D O I
10.1038/s41586-018-0209-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:465 / +
页数:19
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