G-Quadruplexes and the DNA/RNA helicase DHX36 in health, disease, and aging

Abstract

G-Quadruplex (G4) DNA (G4 DNA) and RNA (G4 RNA) are secondary nucleic acid structures that have multiple roles in vital cellular processes. G4 DNA- and RNA-binding proteins and unwinding helicases associate with and regulate G4s during virtually all processes that involve DNA and RNA. DEAH-Box helicase 36 (DHX36), a member of the large DExD/H box helicase family, enzymatically unwinds both G4 DNA and G4 RNA. By exerting its G4 helicase function, DHX36 regulates transcription, genomic stability, telomere maintenance, translation and RNA metabolism. This review will provide an overview of G4s and DHX36, including DHX36's potential role in neuronal development and neurodegeneration. We conclude with a discussion of the possible functions of G4s and DHX36 in the aging brain.

Keywords: DHX36; G-quadruplex DNA; G-quadruplex RNA; G4R1; RHAU.

Figure 1

G-Quadruplex structure, strand arrangement, and interactions with DHX36. (A) Tracts of guanines form planar arrangements via Hoogsten-bonding into G-quartets (blue) and are stabilized by a cation bonded to oxygen molecules in the center (Na⁺ or K⁺). Multiple G-quartets then stack to form G-quadruplexes (G4), in varying strand arrangements. (B) DHX36 regulates telomere maintenance, translation including non-AUG translation and RNA trafficking. DHX36 appears to regulate transcription and likely modulates replication (depicted with the question mark). The question marks also indicate that the direct binding of DHX36 to telomeric G4s and G4s in gene promoters in vivo remains to be shown. DHX36 is also involved in the innate immune response. Thus, multiple biological processes are influenced, including development, immunity, tumorigenesis, aging, and neurodegeneration.

Figure 2

Summary of G-quadruplex-associated dysfunction in various conditions [–50].