DNA-PKcs Is Involved in Ig Class Switch Recombination in Human B Cells.
J Immunol
; 195(12): 5608-15, 2015 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-26546606
ABSTRACT
Nonhomologous end-joining (NHEJ) is one of the major DNA double-strand break repair pathways in mammalian cells and is required for both V(D)J recombination and class switch recombination (CSR), two Ig gene-diversification processes occurring during B cell development. DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) is a component of the classical NHEJ machinery and has a critical function during V(D)J recombination. However, its role in CSR has been controversial. In this study, we examined the pattern of recombination junctions from in vivo-switched B cells from two DNA-PKcs-deficient patients. One of them harbored mutations that did not affect DNA-PKcs kinase activity but caused impaired Artemis activation; the second patient had mutations resulting in diminished DNA-PKcs protein expression and kinase activity. These results were compared with those from DNA-PKcs-deficient mouse B cells. A shift toward the microhomology-based alternative end-joining at the recombination junctions was observed in both human and mouse B cells, suggesting that the classical NHEJ pathway is impaired during CSR when DNA-PKcs is defective. Furthermore, cells from the second patient showed additional or more severe alterations in CSR and/or NHEJ, which may suggest that DNA-PKcs and/or its kinase activity have additional, Artemis-independent functions during these processes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Linfócitos B
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Switching de Imunoglobulina
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Proteínas de Ligação a DNA
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Endonucleases
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Proteína Quinase Ativada por DNA
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Síndromes de Imunodeficiência
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article