title: Proximity to AGCT sequences dictates MMR-independent versus MMR-dependent mechanisms for AID-induced mutation via UNG2.
abstract: AID deaminates C to U in either strand of Ig genes, exclusively producing C:G/G:C to T:A/A:T transition mutations if U is left unrepaired. Error-prone processing by UNG2 or mismatch repair diversifies mutation, predominantly at C:G or A:T base pairs, respectively. Here, we show that transversions at C:G base pairs occur by two distinct processing pathways that are dictated by sequence context. Within and near AGCT mutation hotspots, transversion mutation at C:G was driven by UNG2 without requirement for mismatch repair. Deaminations in AGCT were refractive both to processing by UNG2 and to high-fidelity base excision repair (BER) downstream of UNG2, regardless of mismatch repair activity. We propose that AGCT sequences resist faithful BER because they bind BER-inhibitory protein(s) and/or because hemi-deaminated AGCT motifs innately form a BER-resistant DNA structure. Distal to AGCT sequences, transversions at G were largely co-dependent on UNG2 and mismatch repair. We propose that AGCT-distal transversions are produced when apyrimidinic sites are exposed in mismatch excision patches, because completion of mismatch repair would require bypass of these sites.
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Eddy Sanchai
authors.initials: ES
authors.lastname: Thientosapol
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Sharbeen
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: K K Edwin
authors.initials: KKE
authors.lastname: Lau
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bosnjak
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Durack
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Igor
authors.initials: I
authors.lastname: Stevanovski
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.affiliation: Centenary Institute, Royal Prince Alfred Hospital, Camperdown NSW 2050, and Sydney Medical School, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jolly
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000378:metabolism*; D053843:DNA Mismatch Repair; D004260:DNA Repair; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation; D014498:Uracil / Q000378:metabolism; D051981:Uracil-DNA Glycosidase / Q000235:genetics / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D014498:Uracil; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase