Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.
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.
Howard Hughes Medical Institute, The Children's Hospital and The Center for Blood Research, Boston MA 02115, USA.
Chengming
C
Zhu
Kevin D
KD
Mills
David O
DO
Ferguson
Charles
C
Lee
John
J
Manis
James
J
Fleming
Yijie
Y
Gao
Cynthia C
CC
Morton
Frederick W
FW
Alt
D000818:Animals; D001483:Base Sequence; D002875:Chromosomes / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D005784:Gene Amplification / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016654:Genes, RAG-1; D016259:Genes, myc / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53