title: Stabilised DNA secondary structures with increasing transcription localise hypermutable bases for somatic hypermutation in IGHV3-23.
abstract: Somatic hypermutation (SHM) mediated by activation-induced cytidine deaminase (AID) is a transcription-coupled mechanism most responsible for generating high affinity antibodies. An issue remaining enigmatic in SHM is how AID is preferentially targeted during transcription to hypermutable bases in its substrates (WRC motifs) on both DNA strands. AID targets only single stranded DNA. By modelling the dynamical behaviour of IGHV3-23 DNA, a commonly used human variable gene segment, we observed that hypermutable bases on the non-transcribed strand are paired whereas those on transcribed strand are mostly unpaired. Hypermutable bases (both paired and unpaired) are made accessible to AID in stabilised secondary structures formed with increasing transcription levels. This observation provides a rationale for the hypermutable bases on both the strands of DNA being targeted to a similar extent despite having differences in unpairedness. We propose that increasing transcription and RNAP II stalling resulting in the formation and stabilisation of stem-loop structures with AID hotspots in negatively supercoiled region can localise the hypermutable bases of both strands of DNA, to AID-mediated SHM.
authors.affiliation: School of Kinesiology & Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON M3J 1P3, Canada. bhargavi@yorku.ca
authors.forename: Bhargavi
authors.initials: B
authors.lastname: Duvvuri
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Duvvuri
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wu
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Wu
mesh_terms: D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics*; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012319:RNA Polymerase II / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007135:Immunoglobulin Variable Region; D004247:DNA; D012319:RNA Polymerase II; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase