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PMID: 18775323 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Molecular cell ·Vol. 31 ·No. 5 ·2008-09-05 ·Pages 631-40

Li G, Alt FW, Cheng HL, Brush JW, Goff PH, Murphy MM, Franco S, Zhang Y, Zha S

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.

MeSH Terms
Animals B-Lymphocytes/cytology,immunology,physiology Cells, Cultured DNA Repair DNA Repair Enzymes/genetics,metabolism DNA-Binding Proteins/genetics,metabolism Female Fibroblasts/cytology,physiology Gene Rearrangement Humans Immunoglobulin Class Switching Lymphocytes/cytology,immunology,physiology Mice Mice, Inbred C57BL Mice, Knockout Phenotype Proto-Oncogene Proteins c-bcl-2/genetics,metabolism Recombination, Genetic Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
DNA-Binding Proteins NHEJ1 protein, human Proto-Oncogene Proteins c-bcl-2 Tumor Suppressor Protein p53 DNA Repair Enzymes
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Li Gang
Howard Hughes Medical Institute, The Children's Hospital, The CBR Institute of Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
Alt Frederick W
Cheng Hwei-Ling
Brush James W
Goff Peter H
Murphy Mike M
Franco Sonia
Zhang Yu
Zha Shan
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2008.07.017
Published
2008-09-05
Pages
631-40
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC2630261
Subset
IM
Grants
NIAID NIH HHS · P01 AI035714 · United States
NCI NIH HHS · P01 CA092625 · United States
NIAID NIH HHS · AI35714 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P01 CA092625-07 · United States
NCI NIH HHS · CA92625 · United States
NIAID NIH HHS · P01 AI035714-07 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2008.07.017 PMC Full Text View journal details
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