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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Vydáno v:	Nature Ročník 440; číslo 7080; s. 105 - 109
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 02.03.2006 Nature Publishing Group
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 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