Unfolding the Role of Splicing Factors and RNA Debranching in AID Mediated Antibody Diversification

Abstract

Activated B-cells diversify their antibody repertoire via somatic hypermutation (SHM) and class switch recombination (CSR). SHM is restricted to the variable region, whereas, CSR is confined to the constant region of immunoglobulin (Ig) genes. Activation-induced cytidine deaminase (AID) is a crucial player in the diversification of antibodies in the activated B-cell. AID catalyzes the deamination of cytidine (C) into uracil (U) at Ig genes. Subsequently, low fidelity repair of U:G mismatches may lead to mutations. Transcription is essential for the AID action, as it provides a transient single-strand DNA substrate. Since splicing is a co-transcriptional event, various splicing factors or regulators influence the transcription. Numerous splicing factors are known to regulate the AID targeting, function, Ig transcription, and AID splicing, which eventually influence antibody diversification processes. Splicing regulator SRSF1-3, a splicing isoform of serine arginine-rich splicing factor (SRSF1), and CTNNBL1, a spliceosome interacting factor, interact with AID and play a critical role in SHM. Likewise, a splicing regulator polypyrimidine tract binding protein-2 (PTBP2) and the debranching enzyme (DBR1) debranches primary switch transcripts which later forms G-quadruplex structures, and the S region guide RNAs direct AID to S region DNA. Moreover, AID shows several alternate splicing isoforms, like AID devoid of exon-4 (AIDΔE4) that is expressed in various pathological conditions. Interestingly, RBM5, a splicing regulator, is responsible for the skipping of AID exon 4. In this review, we discuss the role and significance of splicing factors in the AID mediated antibody diversification.

Keywords:

• Activation-induced cytidine deaminase (AID)
• class switch recombination (CSR)
• somatic hypermutation (SHM)
• splicing
• splicing factors

Declaration of Interest

The authors declare that they have no competing interests related to this work.

Additional information

Funding

P. Kodgire received funding from the Department of Science and Technology, Govt. of India, (EMR/2016/003547) and Department of Biotechnology, Govt. of India, (BT/PR20319/BBE/117/189/2016). A. Jaiswal, A. K. Singh and A. Tamrakar thank Council of Scientific and Industrial Research (CSIR), Department of Science and Technology (DST), and University Grants Commission (UGC), Government of India, respectively, for PhD fellowship.