G4 sequences are short fragments of 4-interval triple guanine (G) with frequent and ubiquitous distribution in the genome and RNA transcripts (Figure 1A). The G4 sequences are usually folded into secondary "knot" structure (G4 structure) via Hoogsteen hydrogen bond to exert negative regulation on a variety of biological processes, including DNA replication and transcription, mRNA translation, and telomere maintenance (Figure 1B). There are helicases to relieve the G4 structure barrier, and the known dual DNA/RNA G4 helicases are RHAU, DDX21, and DHX9.The discovery of RHAU dates back to 2004 when Dr. Yoshikuni Nagamine's laboratory in the Friedrich Miescher Institute for Biomedical Research (a part of the Novartis Research Foundation) in Basel, Switzerland, identified a new AU-rich element (ARE)-binding protein that was associated with the ARE fragment of the urokinase plasminogen activator mRNA. 1 This new protein was named RNA helicase associated with AU-rich elements (RHAU) and was found to promote the degradation of ARE-containing mRNAs. 1 Protein sequence analysis of RHAU demonstrated the identical amino acid composition with the ATP-dependent DEAD/DEAH-box helicase 36 (DDX36 or DHX36). 2 One year later, it was found that RHAU possessed the DNA G4 resolving activity to bind and unwind DNA G4 structure, and was hence called G4 resolvase 1 (G4R1). 3 By then, 3 names had been given to this protein: RHAU, DHX36, and G4R1. Afterwards, the G4 resolvase activity of RHAU was extended to RNA molecule through in vitro biochemical analysis. 4 These early pioneering studies have uncovered the primary property of RHAU as DNA/ RNA G4 resolvase/helicase to unwind the G4 secondary structure and laid a solid foundation for elucidating the biological function of RHAU in mouse models. Later on, Dr. Nagamine's group generated the global Rhau knockout mice that were embryonic lethal at around embryonic day 7.5 (E7.5), indicating the essential role of RHAU in mouse development. 5 A following study of hematopoietic-specific Rhau deletion mice revealed