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.

摘要

活化的 B 细胞通过体细胞超突变 (SHM) 和类别转换重组 (CSR) 使其抗体库多样化。SHM 仅限于可变区，而 CSR 仅限于免疫球蛋白 ( Ig ) 基因的恒定区。激活诱导的胞苷脱氨酶 (AID) 是激活 B 细胞中抗体多样化的关键参与者。AID 在Ig处催化胞苷 (C) 脱氨基为尿嘧啶 (U)基因。随后，U:G 错配的低保真修复可能导致突变。转录对于 AID 的作用是必不可少的，因为它提供了一个瞬时的单链 DNA 底物。由于剪接是一个共转录事件，因此各种剪接因子或调节因子会影响转录。已知许多剪接因子可调节 AID 靶向、功能、Ig转录和 AID 剪接，最终影响抗体多样化过程。剪接调节因子 SRSF1-3（一种富含丝氨酸精氨酸的剪接因子 (SRSF1) 的剪接异构体）和 CTNNBL1（一种剪接体相互作用因子）与 AID 相互作用并在 SHM 中发挥关键作用。同样，剪接调节剂聚嘧啶束结合蛋白 2 (PTBP2) 和脱支酶 (DBR1) 使初级开关转录物脱支，随后形成 G-四链体结构，S 区引导 RNA 将 AID 引导至 S 区 DNA。此外，AID 显示了几种交替的剪接同种型，如缺乏外显子 4 的 AID (AIDΔE4)，它在各种病理条件下表达。有趣的是，剪接调节因子 RBM5 负责跳过 AID 外显子 4。在这篇综述中，