Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation.
Telomeres protect chromosome ends from fusion, degradation and recombination. Loss of telomere function has opposite effects on tumorigenesis: apoptosis, which inhibits tumour growth, and genomic instability, which accelerates tumour formation. Here we describe a new mechanism by which short telomeres inhibit tumorigenesis through interference with oncogenic translocations. In mice that are null for both ataxia-telangiectasia-mutated (Atm) and telomerase RNA (mTR), the first generation (G1) Atm-/- mTR-/- mice have a lower rate of tumour formation than Atm-/- mTR+/+ mice. These Atm-/- mTR-/- G1 tumours show no increase in either apoptosis or overall genomic instability. Strikingly, the tumours show a high fraction of translocations containing telomere signals at the translocation junctions. Translocations of the T-cell receptors on chromosome 14, which initiate tumorigenesis, were interrupted by fusion with telomeres. Telomere repeats were also detected at the translocation junctions in pre-malignant thymocytes. We propose that telomere fusion to DNA double-strand breaks competes with the generation of oncogenic translocations and thus reduces tumour formation.
Qi
Ling
L
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Strong
Margaret A
MA
Karim
Baktiar O
BO
Huso
David L
DL
Greider
Carol W
CW
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000737:chemistry / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation; D019457:Chromosome Breakage / Q000235:genetics*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D019672:Genes, T-Cell Receptor / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D005838:Genotype; D017404:In Situ Hybridization, Fluorescence; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D032681:Spectral Karyotyping; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase