[PDF][PDF] Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V (D) J recombination

G Li, FW Alt, HL Cheng, JW Brush, PH Goff… - Molecular cell, 2008 - cell.com
G Li, FW Alt, HL Cheng, JW Brush, PH Goff, MM Murphy, S Franco, Y Zhang, S Zha
Molecular cell, 2008cell.com
Summary 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 …
Summary
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.
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