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Cryo-EM Structure of DHX36 bound to the cMyc DNA G-quadruplex, Class 1
Structural highlights
FunctionDHX36_BOVIN Multifunctional ATP-dependent helicase that unwinds G-quadruplex (G4) structures (PubMed:29899445). Plays a role in many biological processes such as genomic integrity, gene expression regulations and as a sensor to initiate antiviral responses (By similarity). G4 structures correspond to helical structures containing guanine tetrads (PubMed:29899445). Binds with high affinity to and unwinds G4 structures that are formed in nucleic acids (G4-DNA and G4-RNA) (By similarity) (PubMed:29899445). Plays a role in genomic integrity. Converts the G4-RNA structure present in telomerase RNA template component (TREC) into a double-stranded RNA to promote P1 helix formation that acts as a template boundary ensuring accurate reverse transcription (By similarity). Plays a role in transcriptional regulation. Resolves G4-DNA structures in promoters of genes, such as YY1, KIT/c-kit and ALPL and positively regulates their expression (By similarity). Plays a role in post-transcriptional regulation. Unwinds a G4-RNA structure located in the 3'-UTR polyadenylation site of the pre-mRNA TP53 and stimulates TP53 pre-mRNA 3'-end processing in response to ultraviolet (UV)-induced DNA damage (By similarity). Binds to the precursor-microRNA-134 (pre-miR-134) terminal loop and regulates its transport into the synapto-dendritic compartment (By similarity). Involved in the pre-miR-134-dependent inhibition of target gene expression and the control of dendritic spine size (By similarity). Plays a role in the regulation of cytoplasmic mRNA translation and mRNA stability (By similarity). Binds to both G4-RNA structures and alternative non-quadruplex-forming sequence within the 3'-UTR of the PITX1 mRNA regulating negatively PITX1 protein expression (By similarity). Binds to both G4-RNA structure in the 5'-UTR and AU-rich elements (AREs) localized in the 3'-UTR of NKX2-5 mRNA to either stimulate protein translation or induce mRNA decay in an ELAVL1-dependent manner, respectively (By similarity). Also binds to ARE sequences present in several mRNAs mediating exosome-mediated 3'-5' mRNA degradation (By similarity). Involved in cytoplasmic urokinase-type plasminogen activator (uPA) mRNA decay (By similarity). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1 (By similarity). Required for the early embryonic development and hematopoiesis. Involved in the regulation of cardioblast differentiation and proliferation during heart development. Involved in spermatogonia differentiation. May play a role in ossification (By similarity).[UniProtKB:D4A2Z8][UniProtKB:Q8VHK9][UniProtKB:Q9H2U1][1] Publication Abstract from PubMedDEAH-box helicases, which share a structurally conserved ATPase core, function in all facets of eukaryotic gene expression. While most helicases are highly specialized for their substrates, DHX36 (DEAH-box helicase 36) resolves both DNA and RNA G-quadruplexes. To elucidate the molecular basis of this versatility, we have determined cryo-electron microscopy structures of bovine DHX36 bound to a three-tier RNA G-quadruplex and a six-tier DNA G-quadruplex at 2.6 and 3.4 A resolution, respectively. Kinetic and smFRET characterizations of structure-guided mutants indicate a key role for the RecA2 domain of the helicase core in DNA vs. RNA discrimination. Furthermore, our structures show that a sequence-divergent RecA2 domain surface loop synergizes with a DHX36-specific N-terminal extension to orthogonally recognize features that specify G-quadruplexes over other nucleic acid structures. Our analysis suggests that recognizing their folded substrates by DEAH-box helicases may generally involve ornamentations of their structural cores acting synergistically with specialized peripheral elements. Structural basis for dual DNA and RNA specificity of the G-quadruplex-resolving DEAH-box helicase DHX36.,Banco MT, Paul T, Jiang J, Myong S, Ferre-D'Amare AR Cell Rep. 2025 Aug 19;44(9):116136. doi: 10.1016/j.celrep.2025.116136. PMID:40833853[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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