Journal
CELL
Volume 109, Issue 7, Pages 811-821Publisher
CELL PRESS
DOI: 10.1016/S0092-8674(02)00770-5
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Funding
- NCI NIH HHS [CA92625] Funding Source: Medline
- NHLBI NIH HHS [K08 HL67580-02] Funding Source: Medline
- NIAID NIH HHS [AI35714] Funding Source: Medline
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Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAGI1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation.
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