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.
| Original language | English (US) |
|---|---|
| Article number | 1248 |
| Journal | Nature Communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
A licensing step links AID to transcription elongation for mutagenesis in B cells. / Methot, Stephen P.; Litzler, Ludivine C.; Subramani, Poorani Ganesh; Eranki, Anil K.; Fifield, Heather; Patenaude, Anne Marie; Gilmore, Julian C.; Santiago, Gabriel E.; Bagci, Halil; Côté, Jean François; Larijani, Mani; Verdun, Ramiro E; Di Noia, Javier M.
In: Nature Communications, Vol. 9, No. 1, 1248, 01.12.2018.Research output: Contribution to journal › Article
}
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.
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 -