title: Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination.
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.
authors.affiliation: Howard Hughes Medical Institute, The Children's Hospital, The CBR Institute of Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Hwei-Ling
authors.initials: HL
authors.lastname: Cheng
authors.forename: James W
authors.initials: JW
authors.lastname: Brush
authors.forename: Peter H
authors.initials: PH
authors.lastname: Goff
authors.forename: Mike M
authors.initials: MM
authors.lastname: Murphy
authors.forename: Sonia
authors.initials: S
authors.lastname: Franco
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
mesh_terms: 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
chemical_list: D004268:DNA-Binding Proteins; C508551:NHEJ1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D045643:DNA Repair Enzymes
references.citation: Genes Dev. 2004 Jun 1;18(11):1283-92
references.pmid: 15175260
references.citation: Nucleic Acids Res. 2007;35(17):5755-62
references.pmid: 17717001
references.citation: Nature. 2006 Jul 27;442(7101):466-70
references.pmid: 16799570
references.citation: Immunity. 1998 Sep;9(3):367-76
references.pmid: 9768756
references.citation: Mol Cell. 2007 Dec 28;28(6):1093-101
references.pmid: 18158905
references.citation: Cancer Res. 2002 Nov 15;62(22):6395-9
references.pmid: 12438222
references.citation: Cell. 2006 Jan 27;124(2):301-13
references.pmid: 16439205
references.citation: J Biol Chem. 2006 Dec 8;281(49):37517-26
references.pmid: 17038309
references.citation: EMBO J. 1998 Apr 15;17(8):2404-11
references.pmid: 9545251
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2462-7
references.pmid: 12604777
references.citation: J Biol Chem. 2006 May 19;281(20):13857-60
references.pmid: 16571728
references.citation: Cell. 2003 Aug 8;114(3):371-383
references.pmid: 12914701
references.citation: Cell. 2006 Jan 27;124(2):287-99
references.pmid: 16439204
references.citation: Cell. 1998 Dec 23;95(7):891-902
references.pmid: 9875844
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3336-41
references.pmid: 10716718
references.citation: Cell. 2007 Jul 13;130(1):63-75
references.pmid: 17599403
references.citation: Neuroscience. 2007 Apr 14;145(4):1365-74
references.pmid: 16934412
references.citation: EMBO J. 2006 Aug 23;25(16):3880-9
references.pmid: 16874298
references.citation: Nature. 1998 Nov 12;396(6707):173-7
references.pmid: 9823897
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4518-23
references.pmid: 17360556
references.citation: Proc Natl Acad Sci U S A. 2006 May 9;103(19):7378-83
references.pmid: 16670198
references.citation: Nature. 2007 Jun 7;447(7145):725-9
references.pmid: 17554309
references.citation: Nature. 1996 Aug 8;382(6591):551-5
references.pmid: 8700231
references.citation: Science. 2002 May 3;296(5569):922-7
references.pmid: 11934988
references.citation: Cell. 2001 Apr 20;105(2):177-86
references.pmid: 11336668
references.citation: Cell. 2003 Aug 8;114(3):359-70
references.pmid: 12914700
references.citation: Mol Cell. 2002 Dec;10(6):1379-90
references.pmid: 12504013
references.citation: Mol Cell. 2006 Jan 20;21(2):201-14
references.pmid: 16427010
references.citation: Cell. 2002 Mar 22;108(6):781-94
references.pmid: 11955432
references.citation: Nat Rev Immunol. 2008 Apr;8(4):302-12
references.pmid: 18340343
references.citation: Mol Cell. 2008 Feb 29;29(4):488-98
references.pmid: 18313386
references.citation: Cell. 1992 Mar 6;68(5):855-67
references.pmid: 1547487
references.citation: Nature. 2007 Sep 27;449(7161):478-82
references.pmid: 17713479
references.citation: J Biol Chem. 2007 Apr 13;282(15):11155-62
references.pmid: 17317666
references.citation: Immunity. 1997 Jan;6(1):23-33
references.pmid: 9052834
references.citation: Annu Rev Immunol. 2008;26:261-92
references.pmid: 18370922
references.citation: J Exp Med. 2008 Mar 17;205(3):557-64
references.pmid: 18316419
references.citation: EMBO J. 2008 Jan 9;27(1):290-300
references.pmid: 18046455
references.citation: Adv Immunol. 2005;86:43-112
references.pmid: 15705419
references.citation: Proc Natl Acad Sci U S A. 2007 May 8;104(19):7851-6
references.pmid: 17470781
references.citation: Curr Biol. 2000 Feb 10;10(3):165-8
references.pmid: 10679327
references.citation: Cell. 2006 Jan 27;124(2):315-29
references.pmid: 16439206