lmmol · Reviews

Helicase_C (PF00271): Superfamily 2 Helicases from RNA Sensing to Chromatin Remodeling and Genome Stability

lmmol AI Research Collective · Published 2026-06-24 · lmmol:review:PF00271

🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 3,551 papers from lmmol's literature graph. Citations link to their source on PubMed.

Key proteins at a glance
ProteinPapers
Antiviral innate immune response receptor RIG-I79
ATP-dependent RNA helicase DDX3X71
ATP-dependent RNA helicase A71
Chromatin remodeler ATRX58
Interferon-induced helicase C domain-containing protein 156
Probable ATP-dependent RNA helicase DDX1751
Eukaryotic initiation factor 4A-III50
DNA excision repair protein ERCC-649

1. Overview

The Helicase_C domain (PF00271) marks the C-terminal RecA-like lobe of superfamily 2 (SF2) helicases, a vast and functionally diverse clade united by ATP-dependent translocation along nucleic acids. The domain appears across DEAD/DEAH-box RNA helicases, SWI2/SNF2 chromatin remodelers, RecQ DNA helicases, and the cytosolic RIG-I-like RNA sensors. Despite a shared catalytic architecture, these enzymes act in contexts as varied as innate antiviral immunity, RNA interference, pre-mRNA splicing, nucleosome positioning, DNA repair, and biomolecular condensate formation. The substrate is dominated by antiviral RNA sensing, with RIG-I (RIG-I, O95786) and MDA5 (Q9BYX4) the most-cited proteins, alongside the RNAi machinery, chromatin remodelers (ATRX, SMARCA4, CHD1, CHD4, DDM1), and the disease-linked RecQ helicase WRN. This breadth makes Helicase_C a useful lens on how one conserved motor module is repurposed across genome and transcriptome biology.

2. Key proteins

The most heavily studied members in the substrate cluster into functional groups. Innate immunity is anchored by RIG-I, which uses a DExD/H-box helicase domain with intact ATPase activity and a caspase recruitment domain (CARD) to detect cytoplasmic double-stranded RNA and trigger type I interferon [1], and by MDA5, which together with RIG-I and LGP2 forms the RIG-I-like receptor (RLR) family [2][3]. The RNAi and small-RNA pathway is represented by Dicer (Q9UPY3), an RNase III enzyme bearing a helicase domain that generates ~22 nucleotide guide RNAs [4]. RNA metabolism includes DDX3X (O00571), DDX5 (P17844), DDX17 (Q92841), the spliceosomal U5 snRNP 200 kDa helicase (O75643) and DDX39B (Q13838), eIF4A-III (P38919), and the nucleolar helicase DDX21 (Q9NR30). Chromatin remodelers include ATRX (P46100), SMARCA4/BRG1 (P51532), CHD1 (P32657), CHD4 (Q14839), ERCC-6/CSB (Q03468), and the plant remodeler DDM1 (Q9XFH4). Genome-stability DNA helicases include WRN (Q14191) and the RecQ family more broadly. The viral helicase domain within the picornavirus genome polyprotein (P19712) and the bacterial replication-restart helicase PriA (P17888) round out the set.

3. Structural & mechanistic insights

OPEN apo helicaseRecA lobe 1 + RecA lobe 2 / Helicase_C PF00271; weak gripnucleic-acid track5' to 3' strand in open cleftCLOSED ATP-boundtwo lobes clamp strand in inter-lobe cleftpower strokeATP hydrolysis moves motor one position 3'->5'reset and iteraterelease reopens cleft; each cycle is one stepATPADP + Pigrips single strandATP binds clefthydrolysisADP + Pi release
The conserved SF2 helicase motor cycle. Two tandem RecA-like lobes - the second carrying the Helicase_C domain PF00271, which carries the old Helicase_C label - grip a single nucleic-acid strand and close around ATP bound in the inter-lobe cleft. ATP hydrolysis drives a single directional translocation step along the track; release of ADP + Pi reopens the cleft, resetting the motor. Iterated cycles translocate the enzyme 3' to 5' along nucleic acid, displacing the complementary strand and powering unwinding. Accessory domains grafted onto this core, including CARD in RIG-I, chromodomains in Chd1, PAZ/dsRBD in Dicer, and OB-fold in DHX36, couple the motor to each enzyme's specific substrate. OPEN apo, ATP-powered Walker A/B ATP, ATP closes to CLOSED ATP-bound with tight grip, TRANSLOCATED plus ADP Pi, motor steps one position 3'->5', unwinds duplex, displaces 2nd strand.

Across SF2, catalysis depends on two RecA-like lobes that close around ATP to drive directional movement along nucleic acid. RIG-I exemplifies ligand-coupled signaling: the helicase domain senses viral RNA while the CARD transmits the downstream signal, activating NF-kappaB and IRF-3 to induce interferon [1]. In Dicer, two RNase III domains fold via intramolecular dimerization, assisted by flanking PAZ and dsRBD modules, to form a single processing center that cleaves dsRNA into products with 2 nucleotide 3' overhangs [5]. Chromatin remodeling has been visualized directly: a cryo-EM structure of yeast Chd1 bound to a nucleosome shows the bilobal ATPase engaging the second DNA gyre at SHL +2, anchored to the histone H4 N-terminal tail, with the double chromodomain swinging in to close the ATPase and translocate DNA toward the dyad [6]. For specialized substrates, the DEAH/RHA helicase DHX36 resolves G-quadruplexes: a co-crystal structure shows a DHX36-specific N-terminal motif folding into a DNA-binding-induced alpha-helix that, with an OB-fold-like subdomain, selectively binds parallel G-quadruplexes and unfolds them one residue at a time by pulling on a single-stranded tail [7].

4. Disease & therapeutic relevance

Helicase_C members are central to several human diseases. WRN, mutated in Werner's syndrome, is a putative DNA helicase whose loss causes a premature-aging phenotype and early susceptibility to age-related disease [8], while the Bloom's syndrome gene BLM encodes a RecQ-family helicase whose chain-terminating mutations compromise genomic stability [9]. Chromatin remodelers are recurrently disease-linked: mutations in the chromodomain helicase CHD7 cause CHARGE syndrome [10], and unsolved-exome reanalysis implicated the helicase DHX30 among novel Mendelian disease genes [11]. On the therapeutic side, the SWI/SNF ATPase SMARCA2/BRM has been targeted with orally active allosteric dual BRM/BRG1 ATPase inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in BRG1-mutant lung-tumor xenografts, exploiting the dependence of BRG1-deficient cancers on BRM [12]. In DNA repair, DNA polymerase theta inhibitors, including ART558 and the antibiotic novobiocin that binds the POLtheta ATPase domain, elicit synthetic lethality in BRCA-deficient and homologous-recombination-deficient tumors and target PARP-inhibitor resistance [13][14].

5. Recent advances

Modern work has substantially expanded the functional repertoire of these helicases. The RNA helicase DHX9 emerged as a nuclear "RNA resolvase" that binds inverted-repeat Alu elements, suppressing aberrant circular-RNA production and transcriptional rewiring, and interacts in an RNA-independent manner with the interferon-inducible ADAR p150 isoform [15]. DDX3X gained a role as a stress checkpoint: it interacts with NLRP3 to drive inflammasome activation, and its sequestration into stress granules inhibits NLRP3 activation, positioning DDX3X availability as a rheostat for live-or-die cell-fate decisions [16]. Helicases also feed inflammasome sensing in tissue, with Nlrp9b restricting rotavirus in intestinal epithelial cells via the RNA helicase Dhx9, which recognizes short dsRNA stretches to drive caspase-1 maturation and pyroptosis [17]. The YTH-domain helicase YTHDC2 was characterized as an m6A reader that enhances translation and decreases mRNA abundance of its targets, is essential for the mitosis-to-meiosis switch in the germline, and interacts with the small ribosomal subunit and the 5'-3' exoribonuclease XRN1 [18][19][20]. Phase separation entered the field through LAF-1, a DDX3 RNA helicase whose arginine/glycine-rich intrinsically disordered N-terminal domain drives phase separation into P-granule-like droplets with RNA-tunable viscosity [21].

6. Landmark literature

7. Open questions & gaps

The substrate is heavily weighted toward antiviral RNA sensing and the RNAi/small-RNA pathway, with comparatively thin direct coverage of detailed RecQ DNA-helicase mechanism beyond the disease-cloning reports for WRN [8] and BLM [9], so mechanistic structure-function for RecQ unwinding is underrepresented here. Bacterial helicase biology is represented only narrowly by PriA (P17888), with little accompanying mechanistic detail in the substrate. The relationship between the conserved Helicase_C ATPase motor and the divergent N- and C-terminal accessory domains that confer substrate specificity (CARDs, chromodomains, PAZ/dsRBD, OB-folds) is illustrated case by case but not unified across the family in this corpus. How phase separation, inflammasome regulation, and m6A reading mechanistically intersect with canonical helicase translocation remains open, given that the relevant findings [21][16][18] emphasize accessory domains rather than the motor itself. Finally, LGP2's regulatory mechanism within the RLR family is noted as a negative regulator [3] but not structurally resolved in the substrate.

References

  1. Yoneyama M., Kikuchi M., Natsukawa T., Shinobu N. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol 2004. PubMed 3,182×
  2. Loo Y.M., Gale M. Jr. Immune signaling by RIG-I-like receptors. Immunity 2011. PubMed 1,472×
  3. Yoneyama M., Kikuchi M., Matsumoto K., Imaizumi T. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol 2005. PubMed 1,311×
  4. Bernstein E., Caudy A.A., Hammond S.M., Hannon G.J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 2001. PubMed 3,485×
  5. Zhang H., Kolb F.A., Jaskiewicz L., Westhof E. et al. Single processing center models for human Dicer and bacterial RNase III. Cell 2004. PubMed 764×
  6. Farnung L., Vos S.M., Wigge C., Cramer P. Nucleosome-Chd1 structure and implications for chromatin remodelling. Nature 2017. PubMed 209×
  7. Chen M.C., Tippana R., Demeshkina N.A., Murat P. et al. Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36. Nature 2018. PubMed 267×
  8. Yu C.-E., Oshima J., Fu Y.-H., Wijsman E.M. et al. Positional cloning of the Werner's syndrome gene. Science 1996. PubMed 1,416×
  9. Ellis N.A., Groden J., Ye T.-Z., Straughen J. et al. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 1995. PubMed 1,187×
  10. Vissers L.E.L.M., van Ravenswaaij C.M.A., Admiraal R., Hurst J.A. et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat. Genet 2004. PubMed 894×
  11. Eldomery M.K., Coban-Akdemir Z., Harel T., Rosenfeld J.A. et al. Lessons learned from additional research analyses of unsolved clinical exome cases. Genome Med 2017. PubMed 190×
  12. Papillon J.P.N., Nakajima K., Adair C.D., Hempel J. et al. Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers. J. Med. Chem 2018. PubMed 194×
  13. Zatreanu D., Robinson H.M.R., Alkhatib O., Boursier M. et al. Poltheta inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat. Commun 2021. PubMed 307×
  14. Zhou J., Gelot C., Pantelidou C., Li A. et al. A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors. Nat. Cancer 2021. PubMed 288×
  15. Aktas T., Avsar Ilik I., Maticzka D., Bhardwaj V. et al. DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature 2017. PubMed 456×
  16. Samir P., Kesavardhana S., Patmore D.M., Gingras S. et al. DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome. Nature 2019. PubMed 345×
  17. Zhu S., Ding S., Wang P., Wei Z. et al. Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 2017. PubMed 314×
  18. Hsu P.J., Zhu Y., Ma H., Guo Y. et al. Ythdc2 is an N(6)-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res 2017. PubMed 867×
  19. Bailey A.S., Batista P.J., Gold R.S., Chen Y.G. et al. The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline. Elife 2017. PubMed 183×
  20. Kretschmer J., Rao H., Hackert P., Sloan K.E. et al. The m6A reader protein YTHDC2 interacts with the small ribosomal subunit and the 5'-3' exoribonuclease XRN1. RNA 2018. PubMed 212×
  21. Elbaum-Garfinkle S., Kim Y., Szczepaniak K., Chen C.C. et al. The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics. Proc. Natl. Acad. Sci. U.S.A 2015. PubMed 998×
  22. Kato H., Takeuchi O., Sato S., Yoneyama M. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006. PubMed 3,071×
Explore the 2,583 proteins in this family and the underlying literature graph interactively on lmmol.