Abstract

Activation-induced deaminase (AID) mutates the immunoglobulin (Ig) genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR) in B cells, thus underpinning antibody responses. AID mutates a few hundred other loci, but most AID-occupied genes are spared. The mechanisms underlying productive deamination versus non-productive AID targeting are unclear. Here we show that three clustered arginine residues define a functional AID domain required for SHM, CSR, and off-target activity in B cells without affecting AID deaminase activity or Escherichia coli mutagenesis. Both wt AID and mutants with single amino acid replacements in this domain broadly associate with Spt5 and chromatin and occupy the promoter of AID target genes. However, mutant AID fails to occupy the corresponding gene bodies and loses association with transcription elongation factors. Thus AID mutagenic activity is determined not by locus occupancy but by a licensing mechanism, which couples AID to transcription elongation.

Details

Title
A licensing step links AID to transcription elongation for mutagenesis in B cells
Author
Methot, Stephen P 1   VIAFID ORCID Logo  ; Litzler, Ludivine C 2 ; Poorani Ganesh Subramani 3 ; Eranki, Anil K 4 ; Fifield, Heather 5 ; Patenaude, Anne-Marie 6 ; Gilmore, Julian C 4 ; Santiago, Gabriel E 7 ; Bagci, Halil 8 ; Côté, Jean-François 9 ; Larijani, Mani 5 ; Verdun, Ramiro E 10 ; Di Noia, Javier M 11   VIAFID ORCID Logo 

1  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland 
2  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada; Department of Biochemistry and Molecular Medicine, 2900 boul., Montréal, QC, Canada 
3  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada 
4  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada 
5  Department of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada 
6  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada; Genos BioCentar Borongajska cesta 83H, Zagreb, Croatia 
7  Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA 
8  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada 
9  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada 
10  Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; Geriatric Research, Education and Clinical Center, Miami Veterans Affairs Healthcare System, Miami, FL, USA 
11  Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada; Department of Biochemistry and Molecular Medicine, 2900 boul., Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada 
Pages
1-16
Publication year
2018
Publication date
Mar 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-03387-6
ProQuest document ID
2019428523
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.