Altered kinetics of nonhomologous end joining and class switch recombination in ligase IV–deficient B cells
Open Access
- 10 November 2008
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 205 (12), 2745-2753
- https://doi.org/10.1084/jem.20081623
Abstract
Immunoglobulin heavy chain class switch recombination (CSR) is believed to occur through the generation and repair of DNA double-strand breaks (DSBs) in the long and repetitive switch regions. Although implied, the role of the major vertebrate DSB repair pathway, nonhomologous end joining (NHEJ), in CSR has been controversial. By somatic gene targeting of DNA ligase IV (Lig4; a key component of NHEJ) in a B cell line (CH12F3) capable of highly efficient CSR in vitro, we found that NHEJ is required for efficient CSR. Disruption of the Lig4 gene in CH12F3 cells severely inhibits the initial rate of CSR and causes a late cell proliferation defect under cytokine stimulation. However, unlike V(D)J recombination, which absolutely requires NHEJ, CSR accumulates to a substantial level in Lig4-null cells. The data revealed a fast-acting NHEJ and a slow-acting alterative end joining of switch region breaks during CSR.This publication has 28 references indexed in Scilit:
- The Mechanism of Human Nonhomologous DNA End JoiningOnline Journal of Public Health Informatics, 2008
- The catalytic subunit of DNA–protein kinase (DNA-PKcs) is not required for Ig class-switch recombinationProceedings of the National Academy of Sciences of the United States of America, 2007
- Class-switch recombination: interplay of transcription, DNA deamination and DNA repairNature Reviews Immunology, 2004
- DNA-dependent Protein Kinase Activity Is Not Required for Immunoglobulin Class SwitchingThe Journal of Experimental Medicine, 2002
- IgH Class Switch Recombination to IgG1 in DNA-PKcs-Deficient B CellsImmunity, 2002
- Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic miceCurrent Biology, 1998
- Pathological and Physiological Double-Strand BreaksThe American Journal of Pathology, 1998
- Late embryonic lethality and impaired V (D)J recombination in mice lacking DNA ligase IVNature, 1998
- Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class SwitchingThe Journal of Experimental Medicine, 1998
- Ku80 is required for immunoglobulin isotype switchingThe EMBO Journal, 1998