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

KM McBride, V Barreto, AR Ramiro… - The Journal of …, 2004 - rupress.org
KM McBride, V Barreto, AR Ramiro, P Stavropoulos, MC Nussenzweig
The Journal of experimental medicine, 2004rupress.org
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 …
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.
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