Opinion: uracil DNA glycosylase (UNG) plays distinct and non-canonical roles in somatic hypermutation and class switch recombination

Abstract

Activation-induced cytidine deaminase (AID) is essential to class switch recombination (CSR) and somatic hypermutation (SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair complex, is required for CSR. The role of UNG in CSR and SHM is extremely controversial. AID deficiency in mice abolishes both CSR and SHM, while UNG-deficient mice have drastically reduced CSR but augmented SHM raising a possibility of differential functions of UNG in CSR and SHM. Interestingly, UNG has been associated with a CSR-specific repair adapter protein Brd4, which interacts with acetyl histone 4, γH2AX and 53BP1 to promote non-homologous end joining during CSR. A non-canonical scaffold function of UNG, but not the catalytic activity, can be attributed to the recruitment of essential repair proteins associated with the error-free repair during SHM, and the end joining during CSR.

Keywords: AID; Brd4; CSR; NHEJ; SHM; UNG.

Fig. 1.

Differential regulation of CSR and SHM by UNG is catalytic activity independent. (A) UNG deficiency suppresses AID-induced CSR but not mutations at the immunoglobulin (Ig) and non-Ig targets. CSR and SHM efficiencies were calculated from independent studies as indicated in the references. (B) Schematic representation of the UNG structure showing critical residues of the catalytic and the Wxxf motifs. (C) Neither CSR nor SHM correlates well with the catalytic activity of the mutants. Representative UNG mutants show the functional dissociation and distinct regulation of CSR and SHM. Data related to CSR and SHM were taken from references (7, 12, 17, 29, 30, 31) and the catalytic activity was calculated from references (23, 32).

Fig. 2.

SHM and CSR regulation by UNG. (A) AID-induced SSBs initiate SHM by recruiting error-prone polymerase complexes; the UNG-associated BER complex competes with them to drive the faithful repair. (B) AID-induced DSBs initiate CSR; the UNG-associated synapse and recombination factors stabilize the S-S synapse formation to facilitate an efficient recombination. The H4Ac, Brd4, promotes a macromolecular repair complex formation by interaction with γH2AX, 53BP1 and UNG during CSR.