DNA-PKcs Is Involved in Ig Class Switch Recombination in Human B Cells

A Bjorkman, LK Du, K Felgentreff, C Rosner, RP Kamdar, G Kokaraki, Y Matsumoto, EG Davies, Mirjam van der Burg, LD Notarangelo, L Hammarstrom, Q Pan-Hammarstrom

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28 Citations (Scopus)

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.
Original languageUndefined/Unknown
Pages (from-to)5608-5615
Number of pages8
JournalJournal of Immunology
Volume195
Issue number12
DOIs
Publication statusPublished - 2015

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  • EMC MM-02-72-01

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