RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome

Abstract

The immunoglobulin diversification processes of somatic hypermutation and class switch recombination critically rely on transcription coupled targeting of AID to Ig loci in activated B lymphocytes. AID catalyzes deamination of cytidine deoxynucleotides on exposed single stranded DNA. In addition to driving immunoglobulin diversity, promiscuous targeting of AID mutagenic activity poses a deleterious threat to genomic stability. Recent genome-wide studies have uncovered pervasive AID activity throughout the B cell genome. It is increasingly apparent 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 consequences of eukaryotic transcription that lead to early termination, RNA exosome recruitment, and ultimately targeting of AID mutagenic activity.

AID targeting: old mysteries and new challenges

“…Pefanis et al also proposed that divergent transcription generates positive DNA supercoiling ahead of RNA polymerase complexes thus negatively supercoiling the intervening DNA that is divergently transcribing RNA polymerases. This configuration would favor R-loop formation, transcriptional stalling and RNA exosome recruitment [101]. These studies support a model in which RNA exosome-mediated RNA processing events recruit AID to arrested noncoding transcription complexes resulting in mutations or breaks [101].…”

“…This configuration would favor R-loop formation, transcriptional stalling and RNA exosome recruitment [101]. These studies support a model in which RNA exosome-mediated RNA processing events recruit AID to arrested noncoding transcription complexes resulting in mutations or breaks [101]. …”

Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity

“…As discussed in detail in the next two subsections, the RNA exosome complex 57 and the splicing machinery might also play a role 58, 59 .…”

“…Exosome-deficient B cells displayed a reduction in CSR and SHM 63, 64 , implying that exosome-mediated degradation of Igh RNAs facilitates AID activity. The current model 57 posits that convergent and divergent transcription elicit supercoilicity on TSS-proximal DNA 67 , leading to nucleosome eviction. Either the xTSS-RNAs or the exosome may then help stabilize the exposed ssDNA leading to AID attack (Figure 3).…”

Microvesicles and exosome granules and their role in macroorganism.

“…Wykazano, że EG, podobnie jak SG, odgrywają rolę i biorą udział w procesach zapalnych, chorobach autoimmunizacyjnych i nowotworowych (31) oraz w procesach immunologicznych (26). Są one potrzebne dla prawidłowego różnicowania się immunoglobulin (22), jako że biorą udział w regulacji aktywności deaminazy cytydynowej -enzymu niezbędnego do syntezy pirymidyny. EG pochodzące z linii limfocytów B (26) biorą udział w reakcjach odpornościowych, bo posiadają na swej powierzchni antygeny MHC klasy II oraz szereg cząsteczek kostymulujących i adhezyjnych, co dowodzi, że mogą one stymulować limfocyty T z receptorem CD4+.…”