Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells.
The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (IgH)/c-myc coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and c-myc amplification and instead coamplified IgH and N-myc through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target IgH locus translocations to particular oncogenes.
Howard Hughes Medical Institute, Children's Hospital, Department of Genetics, Harvard Medical School, and Center for Blood Research, Boston, MA 02115, USA.
Sean
S
Rooney
JoAnn
J
Sekiguchi
Scott
S
Whitlow
Mark
M
Eckersdorff
John P
JP
Manis
Charles
C
Lee
David O
DO
Ferguson
Frederick W
FW
Alt
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D001483:Base Sequence; D002874:Chromosome Mapping; D004260:DNA Repair; D004720:Endonucleases; D016259:Genes, myc; D016158:Genes, p53; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015448:Leukemia, B-Cell / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000235:genetics*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D013489:Suppression, Genetic / Q000235:genetics*; D015996:Survival Rate; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
D007143:Immunoglobulin Heavy Chains; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D004720:Endonucleases; C473337:Dclre1c protein, mouse