DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination

Sonia Franco, Michael M. Murphy, Gang Li, Tiffany Borjeson, Cristian Boboila, Frederick W. Alt

Research output: Contribution to journalArticlepeer-review

Abstract

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Artemis are classical nonhomologous DNA end-joining (C-NHEJ) factors required for joining a subset of DNA double-strand breaks (DSB), particularly those requiring end processing. In mature B cells, activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) by introducing lesions into S regions upstream of two recombining CH exons, which are processed into DSBs and rejoined by C-NHEJ to complete CSR. The function of DNA-PKcs in CSR has been controversial with some reports but not others showing that DNA-PKcs-deficient mice are significantly impaired for CSR. Artemis-deficient B cells reportedly undergo CSR at normal levels. Overall, it is still not known whether there are any CSR-associated DSBs that require DNA-PKcs and/or Artemis to be joined. Here, we have used an immunoglobulin (Ig)H locus-specific fluorescent in situ hybridization assay to unequivocally demonstrate that both DNA-PKcs and, unexpectedly, Artemis are necessary for joining a subset of AID-dependent DSBs. In the absence of either factor, B cells activated for CSR frequently generate AID-dependent IgH locus chromosomal breaks and translocations. We also find that under specific activation conditions, DNA-PKcs-/- B cells with chromosomal breaks are eliminated or at least prevented from progressing to metaphase via a p53-dependent response. JEM

Original languageEnglish (US)
Pages (from-to)557-564
Number of pages8
JournalJournal of Experimental Medicine
Volume205
Issue number3
DOIs
StatePublished - Mar 17 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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