DHX36
Description
The DHX36 (DEAH-box helicase 36) is a protein-coding gene located on chromosome 3.
DHX36, also known as DEAH box protein 36 (DHX36), MLE-like protein 1 (MLEL1), G4 resolvase 1 (G4R1), or RNA helicase associated with AU-rich elements (RHAU), is an enzyme that in humans is encoded by the DHX36 gene. Structurally, DHX36 is a 1008 amino acid-long modular protein that has been crystallized in a complex with a DNA G-quadruplex. It consists of a ~440-amino acid helicase core comprising all signature motifs of the DEAH/RHA family of helicases with N- and C-terminal flanking regions of ~180 and ~380 amino acids, respectively. Part of the N-terminal flanking region forms an alpha-helix called the DHX36-specific motif, which recognizes the 5'-most G-quadruplex quartet. The OB-fold domain binds to the 3'-most G-tract sugar-phosphate backbone. Like all the DEAH/RHA helicases, the helicase associated domain is located adjacent to the helicase core region and occupies 75% of the C-terminal region. DEAH/RHA proteins are RNA and DNA helicases typically characterized by low processivity translocation on substrates and the capability to bind/unwind non-canonical nucleic acid secondary structures. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this DEAH/RHA protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. DHX36 exhibits a unique ATP-dependent guanine-quadruplex (G4) resolvase activity and specificity for its substrate in vitro.
DHX36 is a multifunctional ATP-dependent helicase that unwinds G-quadruplex (G4) structures, playing a crucial role in various biological processes including genomic integrity, gene expression regulation, and antiviral responses. G4 structures are helical formations comprised of guanine tetrads. DHX36 exhibits high affinity for and unwinds G4 structures in both DNA (G4-DNA) and RNA (G4-RNA). It contributes to genomic integrity by resolving G4-DNA structures, and it facilitates accurate reverse transcription by converting the G4-RNA structure within the telomerase RNA template component (TREC) into a double-stranded RNA, promoting P1 helix formation which acts as a template boundary. DHX36 influences transcriptional regulation by resolving G4-DNA structures in gene promoters, such as YY1, KIT/c-kit, and ALPL, positively regulating their expression. Furthermore, DHX36 plays a role in post-transcriptional regulation by unwinding a G4-RNA structure located in the 3'-UTR polyadenylation site of the pre-mRNA TP53, stimulating TP53 pre-mRNA 3'-end processing in response to ultraviolet (UV)-induced DNA damage. DHX36 also participates in the regulation of cytoplasmic mRNA translation and mRNA stability. It binds to both G4-RNA structures and alternative non-quadruplex-forming sequences within the 3'-UTR of the PITX1 mRNA, negatively regulating PITX1 protein expression. Additionally, DHX36 binds to both G4-RNA structures in the 5'-UTR and AU-rich elements (AREs) localized in the 3'-UTR of NKX2-5 mRNA, either stimulating protein translation or inducing mRNA decay in an ELAVL1-dependent manner. DHX36 binds to ARE sequences present in several mRNAs, mediating exosome-mediated 3'-5' mRNA degradation, and is involved in cytoplasmic urokinase-type plasminogen activator (uPA) mRNA decay. DHX36 is a component of a multi-helicase-TICAM1 complex, acting as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and participating in the activation of a cascade of antiviral responses, including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1. DHX36 is essential for early embryonic development and hematopoiesis, and it plays a role in the regulation of cardioblast differentiation and proliferation during heart development, as well as in spermatogonia differentiation. It may also contribute to ossification.
DHX36 is also known as DDX36, G4R1, MLEL1, RHAU.
