Ubiquitination Events That Regulate Recombination of Immunoglobulin Loci Gene Segments

Jaime Chao,Uttiya Basu,Gerson Rothschild

doi:10.3389/fimmu.2014.00100

Abstract

Programed DNA mutagenesis events in the immunoglobulin (Ig) loci of developing B cells utilize the common and conserved mechanism of protein ubiquitination for subsequent proteasomal degradation to generate the required antigen-receptor diversity. Recombinase proteins RAG1 and RAG2, necessary for V(D)J recombination, and activation-induced cytidine deaminase, an essential mutator protein for catalyzing class switch recombination and somatic hypermutation, are regulated by various ubiquitination events that affect protein stability and activity. Programed DNA breaks in the Ig loci can be identified by various components of DNA repair pathways, also regulated by protein ubiquitination. Errors in the ubiquitination pathways for any of the DNA double-strand break repair proteins can lead to inefficient recombination and repair events, resulting in a compromised adaptive immune system or development of cancer.

Highlights

B cells are developmentally programed to undergo DNA doublestrand breaks (DSBs) in the immunoglobulin (Ig) locus as they generate the antibody diversity required for adaptive immunity
CONCLUDING REMARKS While programed DNA breaks in Ig loci during B-cell development highlights the diverse repertoire of post-translation ubiquitin modifications, ubiquitination processes have shed light on the vital aspects of protein regulation
DNA breaks are essential during B-cell development and for a functional adaptive immune system

Summary

Introduction

B cells are developmentally programed to undergo DNA doublestrand breaks (DSBs) in the immunoglobulin (Ig) locus as they generate the antibody diversity required for adaptive immunity. Though inefficient V(D)J recombination from a RING domain mutation may be a readout of disrupted regulation from RAG1 auto-ubiquitination, ubiquitination of histone H3 may be an important factor during V(D)J recombination to (a) tag the RSS breaks to recruit DNA repair proteins, (b) destabilize the nucleosome or remodel the chromatin for DNA accessibility for repair, (c) promote RAG complex eviction to allow joining machinery to complete coding and signal joints, or (d) promote cell-cycle arrest [13].

Results

Conclusion