Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations

Chengming Zhu, Kevin D. Mills, David O. Ferguson, Charles Lee, John Manis, James Fleming, Yijie Gao, Cynthia C. Morton, Frederick W. Alt

Research output: Contribution to journalArticle

327 Citations (Scopus)

Abstract

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 RAG1/2-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.

Original languageEnglish (US)
Pages (from-to)811-821
Number of pages11
JournalCell
Volume109
Issue number7
DOIs
StatePublished - Jun 28 2002

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Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 12
DNA Breaks
Gene Amplification
Chromosomes
Genetic Recombination
Joining
DNA
Homologous Recombination
Amplification
Drug Resistance
Lymphoma
Tumors
Repair
Neoplasms
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhu, C., Mills, K. D., Ferguson, D. O., Lee, C., Manis, J., Fleming, J., ... Alt, F. W. (2002). Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell, 109(7), 811-821. https://doi.org/10.1016/S0092-8674(02)00770-5

Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. / Zhu, Chengming; Mills, Kevin D.; Ferguson, David O.; Lee, Charles; Manis, John; Fleming, James; Gao, Yijie; Morton, Cynthia C.; Alt, Frederick W.

In: Cell, Vol. 109, No. 7, 28.06.2002, p. 811-821.

Research output: Contribution to journalArticle

Zhu, C, Mills, KD, Ferguson, DO, Lee, C, Manis, J, Fleming, J, Gao, Y, Morton, CC & Alt, FW 2002, 'Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations', Cell, vol. 109, no. 7, pp. 811-821. https://doi.org/10.1016/S0092-8674(02)00770-5
Zhu, Chengming ; Mills, Kevin D. ; Ferguson, David O. ; Lee, Charles ; Manis, John ; Fleming, James ; Gao, Yijie ; Morton, Cynthia C. ; Alt, Frederick W. / Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. In: Cell. 2002 ; Vol. 109, No. 7. pp. 811-821.
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