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

被引:175
作者
McBride, KM
Barreto, V
Ramiro, AR
Stavropoulos, P
Nussenzweig, MC
机构
[1] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA
[2] Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA
关键词
somatic hypermutation; activation-induced deaminase; nucleo-cytoplasmic trasnport; B lymphocytes; Ig class switching;
D O I
10.1084/jem.20040373
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 ora 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.
引用
收藏
页码:1235 / 1244
页数:10
相关论文
共 69 条
[1]   MUTATIONS OF THE CHLORAMPHENICOL ACETYL TRANSFERASE TRANSGENE DRIVEN BY THE IMMUNOGLOBULIN PROMOTER AND INTRON ENHANCER [J].
AZUMA, T ;
MOTOYAMA, N ;
FIELDS, LE ;
LOH, DY .
INTERNATIONAL IMMUNOLOGY, 1993, 5 (02) :121-130
[2]   Increased transcription levels induce higher mutation rates in a hypermutating cell line [J].
Bachl, J ;
Carlson, C ;
Gray-Schopfer, V ;
Dessing, M ;
Olsson, C .
JOURNAL OF IMMUNOLOGY, 2001, 166 (08) :5051-5057
[3]   C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion [J].
Barreto, V ;
Reina-San-Martin, B ;
Ramiro, AR ;
McBride, KM ;
Nussenzweig, MC .
MOLECULAR CELL, 2003, 12 (02) :501-508
[4]   Probing immunoglobulin gene hypermutation with microsatellites suggests a nonreplicative short patch DNA synthesis process [J].
Bertocci, B ;
Quint, L ;
Delbos, F ;
Garcia, C ;
Reynaud, CA ;
Weill, JC .
IMMUNITY, 1998, 9 (02) :257-265
[5]   ELEMENTS REGULATING SOMATIC HYPERMUTATION OF AN IMMUNOGLOBULIN-KAPPA GENE - CRITICAL ROLE FOR THE INTRON ENHANCER MATRIX ATTACHMENT REGION [J].
BETZ, AG ;
MILSTEIN, C ;
GONZALEZFERNANDEZ, A ;
PANNELL, R ;
LARSON, T ;
NEUBERGER, MS .
CELL, 1994, 77 (02) :239-248
[6]   DISTRIBUTION OF MUTATIONS AROUND REARRANGED HEAVY-CHAIN ANTIBODY VARIABLE-REGION GENES [J].
BOTH, GW ;
TAYLOR, L ;
POLLARD, JW ;
STEELE, EJ .
MOLECULAR AND CELLULAR BIOLOGY, 1990, 10 (10) :5187-5196
[7]   Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase [J].
Bransteitter, R ;
Pham, P ;
Scharff, MD ;
Goodman, MF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (07) :4102-4107
[8]   Transcription-targeted DNA deamination by the AID antibody diversification enzyme [J].
Chaudhuri, J ;
Tian, M ;
Khuong, C ;
Chua, K ;
Pinaud, E ;
Alt, FW .
NATURE, 2003, 422 (6933) :726-730
[9]   The apolipoprotein B mRNA editing complex performs a multifunctional cycle and suppresses nonsense-mediated decay [J].
Chester, A ;
Somasekaram, A ;
Tzimina, M ;
Jarmuz, A ;
Gisbourne, J ;
O'Keefe, R ;
Scott, J ;
Navaratnam, N .
EMBO JOURNAL, 2003, 22 (15) :3971-3982
[10]   THE NUCLEAR-PORE COMPLEX [J].
DAVIS, LI .
ANNUAL REVIEW OF BIOCHEMISTRY, 1995, 64 :865-896