RNA processing mechanisms contribute to genome organization and stability in B cells.

RNA processing includes post-transcriptional mechanisms controlling RNA quality and quantity to ensure cellular homeostasis. Noncoding (nc) RNAs that are regulated by these dynamic processes may themselves fulfill effector and/or regulatory functions, and recent studies demonstrated the critical role of RNAs in organizing both chromatin and genome architectures. Furthermore, RNAs can threaten genome integrity when accumulating as DNA:RNA hybrids, but could also facilitate DNA repair depending on the molecular context. Therefore, by qualitatively and quantitatively fine-tuning RNAs, RNA processing contributes directly or indirectly to chromatin states, genome organization, and genome stability. B lymphocytes represent a unique model to study these interconnected mechanisms as they express ncRNAs transcribed from key specific sequences before undergoing physiological genetic remodeling processes, including V(D)J recombination, somatic hypermutation, and class switch recombination. RNA processing actors ensure the regulation and degradation of these ncRNAs for efficient DNA repair and immunoglobulin gene remodeling while failure leads to B cell development alterations, aberrant DNA repair, and pathological translocations. This review highlights how RNA processing mechanisms contribute to genome architecture and stability, with emphasis on their critical roles during B cell development, enabling physiological DNA remodeling while preventing lymphomagenesis.

Unique repetitive nucleic acid structures mirror switch regions in the human IgH locus.

Immunoglobulin (Ig) genes carry the unique ability to be reshaped in peripheral B lymphocytes after these cells encounter a specific antigen. B cells can then further improve their affinity, acquire new functions as memory cells and eventually end up as antibody-secreting cells. Ig class switching is an important change that occurs in this context, thanks to local DNA lesions initiated by the enzyme activation-induced deaminase (AID). Several cis-acting elements of the Ig heavy (IgH) chain locus make it accessible to the AID-mediated lesions that promote class switch recombination (CSR). DNA repeats, with a non-template strand rich in G-quadruplexes (G4)-DNA, are prominent cis-targets of AID and define the so-called "switch" (S) regions specifically targeted for CSR. By analyzing the structure of the human IgH locus, we uncover that abundant DNA repeats, some with a putative G4-rich template strand, are additionally present in downstream portions of the IgH coding genes. These like-S (LS) regions stand as 3' mirror-images of S regions and also show analogies to some previously reported repeats associated with the IgH locus 3' super-enhancer. A regulatory role of LS repeats is strongly suggested by their specific localization close to exons encoding the membrane form of Ig molecules, and by their conservation during mammalian evolution.