Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination.
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.
Li
Gang
G
Howard Hughes Medical Institute, The Children's Hospital, The CBR Institute of Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
Alt
Frederick W
FW
Cheng
Hwei-Ling
HL
Brush
James W
JW
Goff
Peter H
PH
Murphy
Mike M
MM
Franco
Sonia
S
Zhang
Yu
Y
Zha
Shan
S
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015321:Gene Rearrangement; D006801:Humans; D017578:Immunoglobulin Class Switching; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C508551:NHEJ1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D045643:DNA Repair Enzymes
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