Role of genomic instability and p53 in AID-induced c-myc–Igh translocations

Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies 1 . However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between c-myc and the IgH l...

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Bibliographic Details
Published in:Nature Vol. 440; no. 7080; pp. 105 - 109
Main Authors: Ramiro, Almudena R., Jankovic, Mila, Callen, Elsa, Difilippantonio, Simone, Chen, Hua-Tang, McBride, Kevin M., Eisenreich, Thomas R., Chen, Junjie, Dickins, Ross A., Lowe, Scott W., Nussenzweig, Andre, Nussenzweig, Michel C.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 02.03.2006
Nature Publishing Group
Subjects:
Acquired immune deficiency syndrome
AIDS
Animals
B-Lymphocytes - metabolism
Cancer
Cell Line
Cells
Chromosomes
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
Deoxyribonucleic acid
Development and progression
DNA
DNA damage
DNA Damage - genetics
Enzymes
Gene Expression
Genes, Immunoglobulin Heavy Chain - genetics
Genes, myc - genetics
Genetic aspects
Genetic research
Genomic Instability - genetics
Genomics
Health aspects
Humanities and Social Sciences
Hydrolases
Immunoglobulin Class Switching - genetics
Immunoglobulins
Lesions
letter
Lymphocytic leukemia
Mice
Models, Genetic
multidisciplinary
Mutation - genetics
Physiology
Science
Science (multidisciplinary)
Translocation
Translocation, Genetic - genetics
Translocations (Genetics)
Tumor proteins
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumors
United States
ISSN:0028-0836, 1476-4687, 1476-4687, 1476-4679
Online Access:Get full text
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Description
Summary:Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies 1 . However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between c-myc and the IgH locus ( Igh ) are induced in primary B cells within hours of expression of the catalytically active form of activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosine to produce uracil in DNA 2 , 3 . Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks 4 , 5 . The pathway that mediates aberrant joining of c-myc and Igh differs from intrachromosomal repair during immunoglobulin class switch recombination in that it does not require histone H2AX 6 , p53 binding protein 1 (53BP1) 7 , 8 or the non-homologous end-joining protein Ku80 9 . In addition, translocations are inhibited by the tumour suppressors ATM, Nbs1, p19 (Arf) and p53, which is consistent with activation of DNA damage- and oncogenic stress-induced checkpoints during physiological class switching. Finally, we demonstrate that accumulation of AID-dependent, IgH-associated chromosomal lesions is not sufficient to enhance c-myc – Igh translocations. Our findings reveal a pathway for surveillance and protection against AID-dependent DNA damage, leading to chromosomal translocations.
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Author Contributions The last two authors (A.N. and M.C.N.) contributed equally to this work.
These authors contributed equally to this work.
Present Address: Centro de Biologia Molecular Severo Ochoa, Universidad Autonoma de Madrid, Madrid 28049, Spain.
ISSN:0028-0836
1476-4687
1476-4687
1476-4679
DOI:10.1038/nature04495