DHX36

Probable ATP-dependent RNA helicase DHX36 also known as DEAH box protein 36 (DHX36) or MLE-like protein 1 (MLEL1) or 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.[5][6]

DHX36
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2N16, 2N21
Identifiers
Aliases	DHX36, DDX36, G4R1, MLEL1, RHAU, DEAH-box helicase 36
External IDs	OMIM: 612767 MGI: 1919412 HomoloGene: 6356 GeneCards: DHX36
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q25.2 Start 154,272,546 bp[1] End 154,324,487 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 E1 Start 62,468,013 bp[2] End 62,507,004 bp[2]
Gene ontology Molecular function • nucleotide binding • DNA binding • DNA-dependent ATPase activity • GO:0008026 helicase activity • G-quadruplex RNA binding • histone deacetylase binding • G-quadruplex DNA binding • GO:0001948 protein binding • nucleic acid binding • double-stranded RNA binding • hydrolase activity • ATP binding • telomerase RNA binding • RNA binding • single-stranded DNA binding • magnesium ion binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • mRNA 3'-UTR binding • GO:0004003 DNA helicase activity • GO:0034459 3'-5' RNA helicase activity • mRNA 3'-UTR AU-rich region binding • metal ion binding • mRNA 5'-UTR binding • pre-miRNA binding Cellular component • chromosome • chromosome, telomeric region • extracellular exosome • cytosol • cell nucleus • cytoplasm • mitochondrion • Stress granule • nuclear speck • axon • dendrite • cell projection • perikaryon Biological process • RNA processing • regulation of transcription, DNA-templated • ossification • response to exogenous dsRNA • response to virus • transcription, DNA-templated • positive regulation of telomere maintenance • RNA secondary structure unwinding • positive regulation of type I interferon production • positive regulation of transcription from RNA polymerase II promoter • telomerase RNA stabilization • immune system process • positive regulation of myeloid dendritic cell cytokine production • regulation of transcription from RNA polymerase III promoter • regulation of translation • multicellular organism development • spermatogenesis • positive regulation of gene expression • negative regulation of translation • cell differentiation • positive regulation of mRNA 3'-end processing • DNA duplex unwinding • cellular response to heat • cellular response to UV • positive regulation of I-kappaB kinase/NF-kappaB signaling • regulation of mRNA stability • G-quadruplex DNA unwinding • innate immune system • regulation of embryonic development • defense response to virus • positive regulation of cardioblast differentiation • positive regulation of transcription initiation from RNA polymerase II promoter • positive regulation of dendritic spine morphogenesis • 3'-UTR-mediated mRNA destabilization • positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay • positive regulation of hematopoietic progenitor cell differentiation • regulation of transcription from RNA polymerase II promoter involved in spermatogenesis • cellular response to arsenite ion • positive regulation of telomere maintenance via telomere lengthening • positive regulation of intracellular mRNA localization • positive regulation of cytoplasmic translation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	170506	72162
Ensembl	ENSG00000174953 ENSG00000281763	ENSMUSG00000027770
UniProt	Q9H2U1	Q8VHK9
RefSeq (mRNA)	NM_020865 NM_001114397	NM_028136
RefSeq (protein)	NP_001107869 NP_065916	NP_082412
Location (UCSC)	Chr 3: 154.27 – 154.32 Mb	Chr 3: 62.47 – 62.51 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Structurally, DHX36 is a 1008 amino acid-long modular protein that has been crystallized in a complex with a DNA G-quadruplex.[7] 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.[8] 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.[9]

Function

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.[10] 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.[5]

DHX36 exhibits a unique ATP-dependent guanine-quadruplex (G4) resolvase activity and specificity for its substrate in vitro.[11][12] DHX36 displays repetitive unwinding activity as a function of the thermal stability of the G-quadruplex substrate, characteristic of a number of other G-quadruplex resolvases such as the BLM/WRN helicases.[13][14] DHX36 binds G4-nucleic acid with sub-nanomolar affinity and unwinds G4 structures much more efficiently than double-stranded nucleic acid. Consistent with these biochemical observations, DHX36 was also identified as the major source of tetramolecular RNA-resolving activity in HeLa cell lysates.

Previous work showed that DHX36 associates with mRNAs and re-localises to stress granules (SGs) upon translational arrest induced by various environmental stresses.[15][16] A region of the first 105 amino acid was shown to be critical for RNA binding and re-localisation to SGs.

References

1. ENSG00000281763 GRCh38: Ensembl release 89: ENSG00000174953, ENSG00000281763 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000027770 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: DHX36 DEAH (Asp-Glu-Ala-His) box polypeptide 36".
6. Abdelhaleem M, Maltais L, Wain H (June 2003). "The human DDX and DHX gene families of putative RNA helicases". Genomics. 81 (6): 618–22. doi:10.1016/S0888-7543(03)00049-1. PMID 12782131.
7. Chen MC, Tippana R, Demeshkina NA, Murat P, Balasubramanian S, Myong S, Ferré-D'Amaré AR (June 2018). "Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36". Nature. 558 (7710): 465–469. doi:10.1038/s41586-018-0209-9. PMC 6261253. PMID 29899445.
8. Heddi B, Cheong VV, Martadinata H, Phan AT (August 2015). "Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide-quadruplex complex". Proc. Natl. Acad. Sci. U.S.A. 112 (31): 9608–13. doi:10.1073/pnas.1422605112. PMC 4534227. PMID 26195789.
9. Chen WF, Rety S, Guo HL, Dai YX, Wu WQ, Liu NN, Auguin D, Liu QW, Hou XM, Dou SX, Xi XG (March 2018). "Molecular Mechanistic Insights into Drosophila DHX36-Mediated G-Quadruplex Unfolding: A Structure-Based Model". Structure. 26 (3): 403–415.e4. doi:10.1016/j.str.2018.01.008. PMID 29429875.
10. Chen MC, Ferré-D'Amaré AR (15 August 2017). "Structural Basis of DEAH/RHA Helicase Activity". Crystals. 7 (8): 253. doi:10.3390/cryst7080253.
11. Vaughn JP, Creacy SD, Routh ED, Joyner-Butt C, Jenkins GS, Pauli S, Nagamine Y, Akman SA (November 2005). "The DEXH protein product of the DHX36 gene is the major source of tetramolecular quadruplex G4-DNA resolving activity in HeLa cell lysates". The Journal of Biological Chemistry. 280 (46): 38117–20. doi:10.1074/jbc.C500348200. PMID 16150737.
12. Creacy SD, Routh ED, Iwamoto F, Nagamine Y, Akman SA, Vaughn JP (December 2008). "G4 resolvase 1 binds both DNA and RNA tetramolecular quadruplex with high affinity and is the major source of tetramolecular quadruplex G4-DNA and G4-RNA resolving activity in HeLa cell lysates". The Journal of Biological Chemistry. 283 (50): 34626–34. doi:10.1074/jbc.M806277200. PMC 2596407. PMID 18842585.
13. Chen MC, Murat P, Abecassis K, Ferré-D'Amaré AR, Balasubramanian S (February 2015). "Insights into the mechanism of a G-quadruplex-unwinding DEAH-box helicase". Nucleic Acids Res. 43 (4): 2223–31. doi:10.1093/nar/gkv051. PMC 4344499. PMID 25653156.
14. Tippana R, Hwang H, Opresko PL, Bohr VA, Myong S (July 2016). "Single-molecule imaging reveals a common mechanism shared by G-quadruplex-resolving helicases". Proc. Natl. Acad. Sci. U.S.A. 113 (30): 8448–53. doi:10.1073/pnas.1603724113. PMC 4968719. PMID 27407146.
15. Chalupníková K, Lattmann S, Selak N, Iwamoto F, Fujiki Y, Nagamine Y (December 2008). "Recruitment of the RNA helicase RHAU to stress granules via a unique RNA-binding domain". The Journal of Biological Chemistry. 283 (50): 35186–98. doi:10.1074/jbc.M804857200. PMC 3259895. PMID 18854321.
16. Chalupníková, Kateřina (2008). "Characterizing functional domains of the RNA helicase RHAU involved in subcellular localization and RNA interaction" (PDF).

Further reading

• Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O (April 2000). "Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 7 (2): 143–50. doi:10.1093/dnares/7.2.143. PMID 10819331.
• Fu JJ, Li LY, Lu GX (September 2002). "Molecular cloning and characterization of human DDX36 and mouse Ddx36 genes, new members of the DEAD/H box superfamily". Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao Acta Biochimica et Biophysica Sinica. 34 (5): 655–61. PMID 12198572.
• Tran H, Schilling M, Wirbelauer C, Hess D, Nagamine Y (January 2004). "Facilitation of mRNA deadenylation and decay by the exosome-bound, DExH protein RHAU". Molecular Cell. 13 (1): 101–11. doi:10.1016/S1097-2765(03)00481-7. PMID 14731398.
• Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC (May 2004). "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry". Analytical Chemistry. 76 (10): 2763–72. doi:10.1021/ac035352d. PMID 15144186.
• Brown V, Brown RA, Ozinsky A, Hesselberth JR, Fields S (March 2006). "Binding specificity of Toll-like receptor cytoplasmic domains". European Journal of Immunology. 36 (3): 742–53. doi:10.1002/eji.200535158. PMC 2762736. PMID 16482509.
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.

External links

• Group Yoshikuni Nagamine homepage
• Group Steven Akman homepage