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PMID: 11740565 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching.

Nature ·Vol. 414 ·No. 6864 ·2001-12-06 ·Pages 660-665

Petersen S, Casellas R, Reina-San-Martin B, Chen HT, Difilippantonio MJ, Wilson PC, Hanitsch L, Celeste A, Muramatsuk M, Pilch DR, Redon C, Ried T, Bonner WM, Honjo T, Nussenzweig MC, Nussenzweig A

Abstract

Class switch recombination (CSR) is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region (Ch) gene with another. This enables a single variable (V) region gene to be used in conjunction with different downstream Ch genes, each having a unique biological activity. The molecular mechanisms that mediate CSR have not been defined, but activation-induced cytidine deaminase (AID), a putative RNA-editing enzyme, is required for this reaction. Here we report that the Nijmegen breakage syndrome protein (Nbs1) and phosphorylated H2A histone family member X (gamma-H2AX, also known as gamma-H2afx), which facilitate DNA double-strand break (DSB) repair, form nuclear foci at the Ch region in the G1 phase of the cell cycle in cells undergoing CSR, and that switching is impaired in H2AX-/- mice. Localization of Nbs1 and gamma-H2AX to the Igh locus during CSR is dependent on AID. In addition, AID is required for induction of switch region (S mu)-specific DNA lesions that precede CSR. These results place AID function upstream of the DNA modifications that initiate CSR.

MeSH Terms
Animals B-Lymphocytes/immunology,physiology BRCA1 Protein/physiology Base Sequence Cell Cycle Cells, Cultured Cloning, Molecular Cytidine Deaminase/genetics,physiology DNA DNA Repair DNA-Binding Proteins/physiology Histones/physiology Immunoglobulin Class Switching/physiology Immunoglobulin Heavy Chains/genetics Lymphocyte Activation Mice Mice, Inbred C57BL Molecular Sequence Data Mutagenesis Nuclear Proteins/physiology Rad51 Recombinase Recombination, Genetic
Chemicals
BRCA1 Protein DNA-Binding Proteins Histones Immunoglobulin Heavy Chains Nuclear Proteins DNA Rad51 Recombinase Rad51 protein, mouse AICDA (activation-induced cytidine deaminase) Cytidine Deaminase
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Petersen Simone
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Casellas Rafael
Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute, New York, New York 10021, USA.
Reina-San-Martin Bernardo
Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute, New York, New York 10021, USA.
Chen Hua Tang
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Difilippantonio Michael J
Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Wilson Patrick C
Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute, New York, New York 10021, USA.
Hanitsch Leif
Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute, New York, New York 10021, USA.
Celeste Arkady
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Muramatsuk Masamichi
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Pilch Duane R
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Redon Christophe
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ried Thomas
Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Bonner William M
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Honjo Tasuku
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Nussenzweig Michel C
Laboratory of Molecular Immunology, The Rockefeller University, and Howard Hughes Medical Institute, New York, New York 10021, USA.
Nussenzweig André
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
0028-0836
DOI
10.1038/414660a
Published
2001-12-06
Pages
660-665
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4729367
Subset
IM
Grants
Intramural NIH HHS · Z99 CA999999 · United States
External Links
PubMed source DOI: 10.1038/414660a PMC Full Text View journal details
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