Lymphocyte-Specific Compensation for XLF/Cernunnos End-Joining Functions in V(D)J Recombination

Gang Li, Frederick W. Alt, Hwei Ling Cheng, James W. Brush, Peter H. Goff, Mike M. Murphy, Sonia Franco, Yu Zhang, Shan Zha

Research output: Contribution to journalArticle

Abstract

Mutations in XLF/Cernunnos (XLF) cause lymphocytopenia in humans, and various studies suggest an XLF role in classical nonhomologous end joining (C-NHEJ). We now find that XLF-deficient mouse embryonic fibroblasts are ionizing radiation (IR) sensitive and severely impaired for ability to support V(D)J recombination. Yet mature lymphocyte numbers in XLF-deficient mice are only modestly decreased. Moreover, XLF-deficient pro-B lines, while IR-sensitive, perform V(D)J recombination at nearly wild-type levels. Correspondingly, XLF/p53-double-deficient mice are not markedly prone to the pro-B lymphomas that occur in previously characterized C-NHEJ/p53-deficient mice; however, like other C-NHEJ/p53-deficient mice, they still develop medulloblastomas. Despite nearly normal V(D)J recombination in developing B cells, XLF-deficient mature B cells are moderately defective for immunoglobulin heavy-chain class switch recombination. Together, our results implicate XLF as a C-NHEJ factor but also indicate that developing mouse lymphocytes harbor cell-type-specific factors/pathways that compensate for the absence of XLF function during V(D)J recombination.

Original languageEnglish (US)
Pages (from-to)631-640
Number of pages10
JournalMolecular cell
Volume31
Issue number5
DOIs
StatePublished - Sep 5 2008

Keywords

  • DNA
  • MOLIMMUNO

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Li, G., Alt, F. W., Cheng, H. L., Brush, J. W., Goff, P. H., Murphy, M. M., Franco, S., Zhang, Y., & Zha, S. (2008). Lymphocyte-Specific Compensation for XLF/Cernunnos End-Joining Functions in V(D)J Recombination. Molecular cell, 31(5), 631-640. https://doi.org/10.1016/j.molcel.2008.07.017