Cell. 2002 Jun 28;109(7):811-21.

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

Zhu C, Mills KD, Ferguson DO, Lee C, Manis J, Fleming J, Gao Y, Morton CC, Alt FW.

Source

Howard Hughes Medical Institute, The Children's Hospital and The Center for Blood Research, Boston MA 02115, USA.

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.

PMID:: 12110179; [PubMed - indexed for MEDLINE]

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