Depletion of recombination-specific cofactors by the C-terminal mutant of the activation-induced cytidine deaminase causes the dominant negative effect on class switch recombination
© The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes. Studies on in vitro mutagenized AID as well as its mutations in human patients with hyper-IgM (HIGM)-syndrome type II revealed that C-terminal AID mutations were defective in CSR whereas their DNA cleavage and SHM activities remained intact. The C-terminal mutants of AID were speculated to exert the dominant negative effect on wild-type (WT) AID whereas its mechanism remains unknown. We generated the JP41 (R190X) mutation in one allele and a null mutation on the other allele in a mouse B cell line (CH12F3-2A) using CRISPR/Cas9 genome-editing tools and studied the effect of JP41 expression on the function of exogenously introduced WT AID fused with estrogen receptor (AIDER) in AIDJP41/∆/AIDER CH12F3-2A cells. We found that JP41 expression strongly suppressed not only CSR but also Igh/c-Myc chromosomal translocations by AIDER. We showed that the dominant negative effect is not evident at the DNA cleavage step but obvious at both deletional and inversional recombination steps. We also confirmed the dominant negative effect of other C-terminal mutants, JP8Bdel (R183X) and P20 (34-aa insertion at residue 182) in AID-deficient spleen B cells. Finally, we showed that the expression of JP41 reduced the binding of AIDER with its cofactors (hnRNP L, SERBP1 and hnRNP U). Together, these data indicate that dominant negative effect of JP41 on CSR is likely due to the depletion of the CSR-specific RNA-binding proteins from WT AID.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2017 |
|---|---|
| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
|---|---|
| Enthalten in: |
International immunology - 29(2017), 11 vom: 30. Dez., Seite 525-537 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Al Ismail, Azza [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 21.01.2019 Date Revised 21.01.2019 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1093/intimm/dxx061 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM278027156 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM278027156 | ||
| 003 | DE-627 | ||
| 005 | 20231225015626.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1093/intimm/dxx061 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0926.xml |
| 035 | |a (DE-627)NLM278027156 | ||
| 035 | |a (NLM)29136157 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Al Ismail, Azza |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Depletion of recombination-specific cofactors by the C-terminal mutant of the activation-induced cytidine deaminase causes the dominant negative effect on class switch recombination |
| 264 | 1 | |c 2017 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 21.01.2019 | ||
| 500 | |a Date Revised 21.01.2019 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes. Studies on in vitro mutagenized AID as well as its mutations in human patients with hyper-IgM (HIGM)-syndrome type II revealed that C-terminal AID mutations were defective in CSR whereas their DNA cleavage and SHM activities remained intact. The C-terminal mutants of AID were speculated to exert the dominant negative effect on wild-type (WT) AID whereas its mechanism remains unknown. We generated the JP41 (R190X) mutation in one allele and a null mutation on the other allele in a mouse B cell line (CH12F3-2A) using CRISPR/Cas9 genome-editing tools and studied the effect of JP41 expression on the function of exogenously introduced WT AID fused with estrogen receptor (AIDER) in AIDJP41/∆/AIDER CH12F3-2A cells. We found that JP41 expression strongly suppressed not only CSR but also Igh/c-Myc chromosomal translocations by AIDER. We showed that the dominant negative effect is not evident at the DNA cleavage step but obvious at both deletional and inversional recombination steps. We also confirmed the dominant negative effect of other C-terminal mutants, JP8Bdel (R183X) and P20 (34-aa insertion at residue 182) in AID-deficient spleen B cells. Finally, we showed that the expression of JP41 reduced the binding of AIDER with its cofactors (hnRNP L, SERBP1 and hnRNP U). Together, these data indicate that dominant negative effect of JP41 on CSR is likely due to the depletion of the CSR-specific RNA-binding proteins from WT AID | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AID-deficient spleen cells | |
| 650 | 4 | |a CH12F3-2A B cells | |
| 650 | 4 | |a CRISPR/Cas9 mutagenesis | |
| 650 | 4 | |a heterogeneous nuclear ribonucleoproteins | |
| 650 | 4 | |a hyper IgM syndrome | |
| 650 | 7 | |a Cytidine Deaminase |2 NLM | |
| 650 | 7 | |a EC 3.5.4.5 |2 NLM | |
| 700 | 1 | |a Husain, Afzal |e verfasserin |4 aut | |
| 700 | 1 | |a Kobayashi, Maki |e verfasserin |4 aut | |
| 700 | 1 | |a Honjo, Tasuku |e verfasserin |4 aut | |
| 700 | 1 | |a Begum, Nasim A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International immunology |d 1990 |g 29(2017), 11 vom: 30. Dez., Seite 525-537 |w (DE-627)NLM012623598 |x 0953-8178 |7 nnns |
| 773 | 1 | 8 | |g volume:29 |g year:2017 |g number:11 |g day:30 |g month:12 |g pages:525-537 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/intimm/dxx061 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 29 |j 2017 |e 11 |b 30 |c 12 |h 525-537 | ||