RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci

Susannah L. Hewitt, Bu Yin, Yanhong Ji, Julie Chaumeil, Katarzyna Marszalek, Jeannette Tenthorey, Giorgia Salvagiotto, Natalie Steinel, Laura B. Ramsey, Jacques Ghysdael, Michael A. Farrar, Barry P. Sleckman, David G. Schatz, Meinrad Busslinger, Craig H. Bassing, Jane A. Skok

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

Coordinated recombination of homologous antigen receptor loci is thought to be important for allelic exclusion. Here we show that homologous immunoglobulin alleles pair in a stage-specific way that mirrors the recombination patterns of these loci. The frequency of homologous immunoglobulin pairing was much lower in the absence of the RAG-1-RAG-2 recombinase and was restored in Rag1-/- developing B cells with a transgene expressing a RAG-1 active-site mutant that supported DNA binding but not cleavage. The introduction of DNA breaks on one immunoglobulin allele induced ATM-dependent repositioning of the other allele to pericentromeric heterochromatin. ATM activated by the cleaved allele acts in trans on the uncleaved allele to prevent biallelic recombination and chromosome breaks or translocations.

Original languageEnglish (US)
Pages (from-to)655-664
Number of pages10
JournalNature immunology
Volume10
Issue number6
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
We thank M. Nussenzweig (Rockefeller University) for BAC HG and members of the Skok lab for critical reading of this manuscript. Supported by the Wellcome Trust (085096 to J.A.S.), the New York University School of Medicine (J.A.S.), the US National Institutes of Health (R37 AI32524 to D.G.S.; R01 GM086852A to J.A.S.; R01 CA125195 to C.H.B.; and RO1 AI050737 to M.A.F.), the Pew Scholars Program (C.H.B. and M.A.F.), the Cancer Research Institute (M.A.F.), the Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology (B.Y.), Boehringer Ingelheim (M.B.), Genome Research in Austria (M.B.) and the Howard Hughes Medical Institute (D.G.S.).

Funding Information:
In the version of this article initially published, some of the funding was stated incorrectly or missing; the Competing Financial Interests section was missing; and the citation to reference 15 was missing. The correct funding statement should be as follows: Supported by the Wellcome Trust (085096 to J.A.S.), the New York University School of Medicine (J.A.S.), the US National Institutes of Health (R37 AI32524 to D.G.S.; R01 GM086852A to J.A.S.; R01 CA125195 to C.H.B.; and RO1 AI050737 to M.A.F.), the Pew Scholars Program (C.H.B. and M.A.F.), the Cancer Research Institute (M.A.F.), the Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology (B.Y.), Boehringer Ingelheim (M.B.), Genome Research in Austria (M.B.) and the Howard Hughes Medical Institute (D.G.S.). The correct Competing Financial Interests statement should be “The authors declare competing financial interests”; in the PDF, the statement also includes “details accompany the full-text HTML version of the paper at http://www.nature.com/natureimmunology/.” The citation for reference 15 should be on the first page as follows: “Studies of the rearrangement status of Igh alleles in mature B cell hybridomas and in developing B cells that have been transformed by Abelson murine leukemia virus15 have suggested….” The errors have been corrected in the HTML and PDF versions of the article.

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