TY - JOUR
T1 - A licensing step links AID to transcription elongation for mutagenesis in B cells
AU - Methot, Stephen P.
AU - Litzler, Ludivine C.
AU - Subramani, Poorani Ganesh
AU - Eranki, Anil K.
AU - Fifield, Heather
AU - Patenaude, Anne Marie
AU - Gilmore, Julian C.
AU - Santiago, Gabriel E.
AU - Bagci, Halil
AU - Côté, Jean François
AU - Larijani, Mani
AU - Verdun, Ramiro E.
AU - Di Noia, Javier M.
N1 - Funding Information:
We thank Dr. N. Francis for critical reading and Dr. F. Robert, Dr. A. Orthwein and Dr. A. Zahn for discussions. We thank Jean-Felix Côté for technical help and the assistance of D. Fillion with microscopy, E. Massicotte, J. Lord, J. Leconte and P. St-Onge with flow cytometry, D. Faubert with mass spectrometry and M. Cawthorne and E. Thivierge with animal care. We thank Dr. M. Neuberger, Dr. A. Orthwein, Dr. D. Durocher, Dr. R. Pavri and Dr. T. Honjo for sharing reagents. This work was funded by grants from the Cancer Research Society (to J.M.D.N.) and Canadian institutes of Health research (MOP130535 to J.M.D.N., MOP111132 to M.L.), CCSRI innovation grant 702145 (to M.L.), NIH R01GM121595 (to R.E.V.) and a Discovery grant from The Natural Sciences and Engineering Research Council of Canada (to J.-F.C.). S.P.M. and H.B. were supported by doctoral training awards from the Fonds de Recherche du Québec-Santé. S.P.M. and L.C. L. were supported by doctoral fellowships from the Cole Foundation. J.-F.C. holds the Transat Chair in Breast Cancer Research and is supported by an FRQS Senior investigator career award. J.M.D.N. holds the Canada Research Chair in Genetic Diversity.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-03387-6
DO - 10.1038/s41467-018-03387-6
M3 - Article
C2 - 29593215
AN - SCOPUS:85044504719
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1248
ER -