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PMID: 15117971 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase.

The Journal of experimental medicine ·Vol. 199 ·No. 9 ·2004-05-03 ·Pages 1235-44

McBride KM, Barreto V, Ramiro AR, Stavropoulos P, Nussenzweig MC

Abstract

Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated in activated B lymphocytes by activation-induced deaminase (AID). AID is thought to make lesions in DNA by deaminating cytidine residues in single-stranded DNA exposed by RNA polymerase during transcription. Although this must occur in the nucleus, AID is found primarily in the cytoplasm. Here we show that AID is actively excluded from the nucleus by an exportin CRM1-dependent pathway. The AID nuclear export signal (NES) is found at the carboxyl terminus of AID in a region that overlaps a sequence required for CSR but not SHM. We find that AID lacking a functional NES causes more hypermutation of a nonphysiologic target gene in transfected fibroblasts. However, the NES does not impact on the rate of mutation of immunoglobulin genes in B lymphocytes, suggesting that the AID NES does not limit AID activity in these cells.

MeSH Terms
Amino Acid Sequence Aminohydrolases/metabolism Animals B-Lymphocytes/immunology Base Sequence Cell Line Cells, Cultured DNA Primers Enzyme Activation Humans Karyopherins/chemistry,genetics,metabolism Mice Molecular Sequence Data Peptide Fragments/chemistry Polymerase Chain Reaction Protein Transport Receptors, Cytoplasmic and Nuclear Recombinant Proteins/chemistry,metabolism Sequence Alignment Somatic Hypermutation, Immunoglobulin/genetics,immunology
Chemicals
DNA Primers Karyopherins Peptide Fragments Receptors, Cytoplasmic and Nuclear Recombinant Proteins exportin 1 protein Aminohydrolases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
McBride Kevin M
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA.
Barreto Vasco
Ramiro Almudena R
Stavropoulos Pete
Nussenzweig Michel C
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20040373
Published
2004-05-03
Epub
2004-00-26
Pages
1235-44
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2211910
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20040373 PMC Full Text View journal details
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