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J Exp Med. 2004 May 3;199(9):1235-44. Epub 2004 Apr 26.

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

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  • 1Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA.

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.

PMID:
15117971
[PubMed - indexed for MEDLINE]
PMCID:
PMC2211910
Free PMC Article

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