Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase

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Abstract

Activation-induced cytidine deaminase (AID) is essential to classswitch recombination (CSR) and somatic hypermutation (SHM) in both V region SHM and S region SHM (s-SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair (BER) complex, is required for CSR. Strikingly, however, UNG deficiency causes augmentation of SHM, suggesting involvement of distinct functions of UNG in SHMand CSR. Here,we show that noncanonical scaffold functions of UNG regulate s-SHM negatively and CSR positively. The s-SHM suppressive function of UNG is attributed to the recruitment of faithful BER components at the cleaved DNA locus, with competition against error-prone polymerases. By contrast, the CSR-promoting function of UNG enhances AID-dependent S-S synapse formation by recruiting p53-binding protein 1 and DNAdependent protein kinase, catalytic subunit. Several loss-of-catalysis mutants of UNG discriminated CSR-promoting activity from s-SHM suppressive activity. Taken together, the noncanonical function of UNG regulates the steps after AID-induced DNA cleavage: errorprone repair suppression in s-SHM and end-joining promotion in CSR.

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Yousif, A. S., Stanlie, A., Mondal, S., Honjo, T., & Begum, N. A. (2014). Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase. Proceedings of the National Academy of Sciences of the United States of America, 111(11). https://doi.org/10.1073/pnas.1402391111

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