A licensing step links AID to transcription elongation for mutagenesis in B cells

Stephen P. Methot, Ludivine C. Litzler, Poorani Ganesh Subramani, Anil K. Eranki, Heather Fifield, Anne-Marie Patenaude, Julian C. Gilmore, Gabriel E. Santiago, Halil Bagci, Jean-François Côté, Mani Larijani, Ramiro E. Verdun and Javier M. Di Noia ()
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Stephen P. Methot: Institut de Recherches Cliniques de Montréal
Ludivine C. Litzler: Institut de Recherches Cliniques de Montréal
Poorani Ganesh Subramani: Institut de Recherches Cliniques de Montréal
Anil K. Eranki: Institut de Recherches Cliniques de Montréal
Heather Fifield: Memorial University of Newfoundland
Anne-Marie Patenaude: Institut de Recherches Cliniques de Montréal
Julian C. Gilmore: Institut de Recherches Cliniques de Montréal
Gabriel E. Santiago: University of Miami
Halil Bagci: Institut de Recherches Cliniques de Montréal
Jean-François Côté: Institut de Recherches Cliniques de Montréal
Mani Larijani: Memorial University of Newfoundland
Ramiro E. Verdun: University of Miami
Javier M. Di Noia: Institut de Recherches Cliniques de Montréal

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03387-6

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