The cell cycle restricts activation-induced cytidine deaminase activity to early G1

Abstract

Wang et al. show that antibody gene deamination by activation-induced cytidine deaminase (AID) is restricted to a short time window in early G1 as a result of AID’s transient nuclear localization and accessibility of the target sites.

The microanatomic segregation of selection by apoptosis in the germinal center

“…2I, J; bottom). This observation is consistent with reports that AID is expressed at higher levels and accesses DNA in proliferating DZ B cells (5, 16, 17). Although a majority of non-functional apoptotic DZ BCRs carried stop codons (63% and 69% in NP-OVA- and GT1.1-elicited GCs, respectively), a significant fraction (37% and 31%, respectively) was out-of-frame due to nucleotide insertions or deletions (fig.…”

Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational Asymmetry

“…Collectively, these analyses illustrate that removal of noncoding RNAs associated with the antisense DNA strand by RNA exosome requires the activity of Mtr4 and Setx, without which there is an increased level of ssDNA on the DNA sense strand (non-transcribed/non-template DNA). As would be expected in the case of bidirectional transcription or convergent transcription at switch sequences (Meng et al, 2014; Pefanis et al, 2014; Wang et al, 2016), the possibility exists that ncRNAs associated with the antisense DNA strand are processed by the RNA exosome complex similarly to germline transcripts and provide another mechanism of antisense DNA strand AID access by R-loop formation. However, such an interpretation needs to be approached carefully, as ncRNAs that are associated with the antisense DNA strand are significantly lower in expression level than germline transcripts associated with the sense DNA strand, based on RNA-sequencing data obtained both in the 5′Smu region as well as in the intronic Iμ and Eμ regions (Fig.…”

“…Displacement from the nuclear center of the IgH locus could be due to many factors including DNA motion that is associated with passage of time as chromosomes accomplish the long distance DNA interactions required during recombination (Lucas et al, 2014). AID is recruited into the nucleus of B cells during the mitotic phase of the cell cycle (Wang et al, 2016) and mutates DNA predominantly in the early G1 phase (Rush et al, 2004; Wang et al, 2016). We postulate that as B cells recover from M phase and enter G1 phase, chromosome 12 (containing IgH ) associates with AID and complexes with RNA exosome, Mtr4, and other relevant factors to orchestrate CSR.…”

EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop

“…This is important not only to understand the cell biology of the GC reaction but also because proliferation is intimately linked and required for immunoglobulin affinity maturation 1, 2 . Our data delineate a model whereby EZH2 drives unrestricted cycling of GC B cells by directly repressing cyclin-dependent kinase inhibitor gene CDKN1A .…”

“…GC B cells are unique in their ability to replicate at an accelerated rate, while undergoing somatic hypermutation 1 . Importantly, cell cycle progression is required for the enzyme AICDA to genetically modify the immunoglobulin gene variable regions 2 . Thus rapid proliferation of GC B cells is intimately linked to, and required for, the humoral immune response 1 .…”