CommunicationsThe G-Quadruplex-Specific RNA Helicase DHX36 Regulates p53 Pre-mRNA 3′-End Processing Following UV-Induced DNA Damage

- DHX36 (RHAU/G4R1) is necessary to maintain p53 pre-mRNA 3′-end processing (polyadenylation) following UV.
- Impaired p53 pre-mRNA 3′-end processing following depletion of DHX36 results in a loss of p53 protein in response to UV-induced DNA damage.
- DHX36 binds to the p53 RNA G4-forming sequence.
- Stabilization of the p53 RNA G4 impairs pre-mRNA 3′-end processing following UV.

Pre-mRNA 3′-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3′-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3′-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3′-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands (PNADOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3′-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV.

Graphical Abstract116