Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions.
Although nonhomologous end-joining (NHEJ) deficiency has been shown to accelerate lymphoma formation in mice, its role in suppressing tumors in cells that do not undergo V(D)J recombination is unclear. Utilizing a tumor-prone mouse strain (ink4a/arf(-/-)), we examined the impact of haploinsufficiency of a NHEJ component, DNA ligase IV (Lig4), on murine tumorigenesis. We demonstrate that lig4 heterozygosity promotes the development of soft-tissue sarcomas that possess clonal amplifications, deletions, and translocations. That these genomic alterations are relevant in tumorigenesis is supported by the finding of frequent mdm2 amplification, a known oncogene in human sarcoma. Together, these findings support the view that loss of a single lig4 allele results in NHEJ activity being sufficiently reduced to engender chromosomal aberrations that drive non-lymphoid tumorigenesis.
Sharpless
N E
NE
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Ferguson
D O
DO
O'Hagan
R C
RC
Castrillon
D H
DH
Lee
C
C
Farazi
P A
PA
Alson
S
S
Fleming
J
J
Morton
C C
CC
Frank
K
K
Chin
L
L
Alt
F W
FW
DePinho
R A
RA
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002872:Chromosome Deletion; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics* / Q000502:physiology; D005347:Fibroblasts; D005784:Gene Amplification / Q000235:genetics*; D017353:Gene Deletion; D006579:Heterozygote; D019656:Loss of Heterozygosity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D016296:Mutagenesis / Q000235:genetics; D012509:Sarcoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000607893:LIG4 protein, human; D025803:Tumor Suppressor Protein p14ARF; D011088:DNA Ligases; D000072481:DNA Ligase ATP