This proposal is directed towards the understanding of the mechanisms that govern antibody diversification during an adaptive immune response. Antibodies are polypeptide complexes produced from B-lymphocytes that are present in the bodily fluids of vertebrates, and are used by the immune system to identify and neutralize various foreign antigens. Newly generated B cells migrate from bone- marrow to secondary lymphoid organs where they encounter antigens, and are stimulated to further undergo two Immunoglobulin (Ig) gene alterations known as class switch recombination (CSR) and somatic hypermutation (SHM). CSR is a B cell-specific DNA rearrangement reaction that replaces an Ig heavy chain constant region gene (CH) from C? with other downstream CH exons so that secondary isotypes (IgG, IgA etc) with different effector functions are generated. SHM, on the other hand, introduces point mutations into V genes at a very high rate, ultimately leading to increased antibody affinity. Though two distinct processes, CSR and SHM absolutely require transcription through the relevant Ig loci and activity of a single-strand DNA deaminase, Activation Induced cytidine Deaminase (AID). AID introduces point mutations in the at specific Ig locus DNA sequences (switch (S) sequences or variable regions (V) genes) that are then converted to DNA lesions (double-strand breaks or mutations) to initiate CSR and SHM. The mechanism by which AID introduces these mutations in the Ig locus in a regulated fashion is an active field of investigation. Our recent studies indicate that AID utilizes the cellular non-codin RNA degradation/processing complex, RNA exosome, to mutate both strands of substrate DNA sequences. Using a combination of modern proteomic approaches, high- throughput genomics and mouse genetics we continue to study the mechanism of function of RNA exosome/AID complex function during CSR and SHM. Understanding the mechanism of AID function is of paramount importance. Human patients with inactivating mutations in the AID gene suffer from Hyper-IgM syndrome (HIGM2), whereas aberrant expression of AID may lead to various B and T cell malignancies. Understanding of AID function in B-lymphocytes will allow treatment of these patients with directed clinical therapies.
This proposal investigates the mechanism of regulation of the proto-oncogene Activation Induced cytidine Deaminase (AID) by the non-coding RNA degradation complex, RNA exosome. AID is essential for initiating the class switch recombination (CSR) and somatic hypermutation (SHM), two processes required for generation of antibodies that participate in bio-defense via adaptive immune response.
| Zou, Fagui; Wang, Xu; Han, Xinxin et al. (2018) Expression and Function of Tetraspanins and Their Interacting Partners in B Cells. Front Immunol 9:1606 |
| Rothschild, Gerson; Basu, Uttiya (2017) Lingering Questions about Enhancer RNA and Enhancer Transcription-Coupled Genomic Instability. Trends Genet 33:143-154 |
| Skamagki, Maria; Zhang, Cheng; Ross, Christian A et al. (2017) RNA Exosome Complex-Mediated Control of Redox Status in Pluripotent Stem Cells. Stem Cell Reports 9:1053-1061 |
| Lim, Junghyun; Giri, Pankaj Kumar; Kazadi, David et al. (2017) Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational Asymmetry. Cell 169:523-537.e15 |
| Rialdi, Alexander; Hultquist, Judd; Jimenez-Morales, David et al. (2017) The RNA Exosome Syncs IAV-RNAPII Transcription to Promote Viral Ribogenesis and Infectivity. Cell 169:679-692.e14 |
| Laffleur, Brice; Basu, Uttiya; Lim, Junghyun (2017) RNA Exosome and Non-coding RNA-Coupled Mechanisms in AID-Mediated Genomic Alterations. J Mol Biol 429:3230-3241 |
| Rothschild, Gerson; von Krusenstiern, A Nikolai; Basu, Uttiya (2015) Malaria-Induced B Cell Genomic Instability. Cell 162:697-8 |
| Pefanis, Evangelos; Basu, Uttiya (2015) RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome. Adv Immunol 127:257-308 |
| Pefanis, Evangelos; Wang, Jiguang; Rothschild, Gerson et al. (2015) RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity. Cell 161:774-89 |
| Sun, Jianbo; Wang, Jiguang; Pefanis, Evangelos et al. (2015) Transcriptomics Identify CD9 as a Marker of Murine IL-10-Competent Regulatory B Cells. Cell Rep 13:1110-1117 |
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