The immunoglobulin diversification processes of somatic hypermutation and class switch recombination critically rely on transcription coupled targeting of AID to loci in activated B lymphocytes. that AID activity is frequently targeted to genomic loci undergoing early transcription termination where RNA exosome promotes the resolution of stalled transcription complexes via co-transcriptional RNA degradation mechanisms. Here we review aspects and effects of eukaryotic transcription that lead to early termination RNA exosome recruitment and ultimately targeting of AID mutagenic activity. 1 OVERVIEW OF AID FUNCTION IN IMMUNOGLOBULIN DIVERSIFICATION All species of life have evolved various defense mechanisms providing protection against pathogens Araloside V and other nonself antigens. The Araloside V majority of species rely almost exclusively on germline encoded non-specific approaches collectively referred to as the innate immune system which is fully operable prior to pathogen encounter. However vertebrate species have evolved an additional mechanism of immunity including specific acknowledgement of pathogen during the course of an immune response (Hirano et al. 2011 This latter process is known as the adaptive immune response and entails the introduction of somatic genome alterations to generate high affinity antigen acknowledgement. Immunoglobulin (Ig) which entirely comprises the humoral arm of the adaptive immune system is usually encoded within discontinuous gene segments that require assembly through an sophisticated mechanism in B cells including combinatorial rearrangement of heavy and light chain loci known as V(D)J recombination. Naive B cells that productively rearrange their heavy and light chain loci resulting in functional non-autoreactive surface immunoglobulin (BCR) exit the bone marrow and circulate in the periphery. Upon encountering cognate antigen and appropriate T cell help within germinal centers activated B cells expose additional somatic mutations in their variable regions through the process of somatic hypermutation (SHM) and undergo Ig isotype switching through the process of class switch recombination (CSR). SHM coupled with intercellular B cell selection defines the physiological phenomenon of affinity maturation a process where the affinity of serum Ig towards antigen increases over time during an immune response. CSR prospects to altered Ig effector function by specifically replacing the germline encoded IgM heavy chain Araloside V isotype of naive B cells with a different isotype such as IgG IgE or IgA. Each of these isotypes differs in their accumulation within various bodily fluids their molecular stoichiometry and ability to interact with different cell types according to isotype specific Fc receptor expression. Activation induced cytidine deaminase (AID) is specifically induced in germinal center B cells (Muramatsu et al. 1999 and is strictly required during SHM and CSR (Muramatsu Araloside V et al. 2000 Revy et al. 2000 In its absence both Ig diversification processes are entirely ablated and loci are devoid of somatic DNA mutation. Many lines of biochemical and genetic evidence have exhibited single stranded DNA (ssDNA) as the physiological substrate of AID (Bransteitter et al. 2003 Dickerson et al. 2003 Petersen-Mahrt Harris and Neuberger 2002 In addition AID dependent deoxyuridine residues have been detected at multiple loci through biochemical methods (Maul et al. 2011 As the substrate specificity of AID is usually towards ssDNA a key question was the context in which AID substrates become accessible. Preceding the discovery of AID transcription of target sequences had been implicated as a critical step in the hypermutation process. It was shown that this variable region exon of a germline rearranged heavy chain transgene in mouse B cells contained much fewer mutations when its promoter was deleted (Fukita Jacobs and Rajewsky 1998 However targeting of SHM to variable regions was not specifically determined by the nature of the promoter as transgenes made up of heterologous promoters were still capable of undergoing MLL3 SHM (Betz et al. 1994 Tumas-Brundage and Manser 1997 Later experiments using drug inducible transgenes in a hypermutating cell collection indicated that this rates of SHM and CSR directly correlated with the rate of transgene transcription (Bachl et al. 2001 Lee et al. 2001 Another crucial experiment provided evidence that the nature of the transcribed sequence variable region exons in the case of SHM does not determine targeting specificity. Here SHM was evaluated in B cell hybridomas made up of a.