title: Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase.
abstract: Activation-induced cytidine deaminase (AID) is essential to class-switch 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 SHM and 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 DNA-dependent 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: error-prone repair suppression in s-SHM and end-joining promotion in CSR.
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Yousif
authors.forename: Andre
authors.initials: A
authors.lastname: Stanlie
authors.forename: Samiran
authors.initials: S
authors.lastname: Mondal
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Nasim A
authors.initials: NA
authors.lastname: Begum
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D059766:DNA End-Joining Repair / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005453:Fluorescence; D049452:Green Fluorescent Proteins / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology*; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D049452:Green Fluorescent Proteins; D051981:Uracil-DNA Glycosidase; D003564:Cytidine Deaminase
keywords: NHEJ; synapsis