The DEAH-box helicase RHAU regulates immunoglobulin class switch recombination

Abstract During a humoral immune response, B cells produce alternative immunoglobulin isotypes (IgG, IgA, IgE) through class switch recombination (CSR). Initiation of CSR requires AID-mediated deamination of switch (S) regions in the immunoglobulin heavy chain (IgH) locus. Although G-quadruplex(G4)-forming S region RNAs bind AID and localize AID to S region DNA sequences, the molecular mechanism that regulates the transition of AID binding from RNA to DNA remains uncharacterized. Highly stable G4 structures necessitate helicases to unwind the G-G hydrogen bonds, which in turn may permit the base-pairing of the S transcript to the complementary DNA sequence in the IgH locus during CSR. An S region RNA pull-down assay identified the RNA Helicase associated with AU-rich element (RHAU), a DEAH-box RNA helicase, as an S transcript binding protein. To examine the role of RHAU in CSR, we genetically deleted a floxed RHAU allele in B cells of mice using CD23-Cre. Conditional deletion of RHAU in B cells reduced CSR in vivo and in vitro to approximately 50% of wild-type controls. This data suggests that RHAU plays an important role in CSR. We hypothesize that RHAU unwinds G4 in S transcripts to facilitate the handoff of AID from G4-RNA to S region DNA during CSR. Supported by The National Cancer Institute (2U54CA132378) and The National Institute of General Medical Sciences (1SC1GM132035-01)