Telomeres protect chromosome ends from fusion, and loss of telomeres can lead to genomic instability and tumour formation. However, telomere loss can also cause apoptosis. Carol Greider and colleagues now show that short telomeres can inhibit tumorigenesis by fusing to DNA double-strand breaks, preventing oncogenic chromosome translocations.

The authors studied a mouse model that was null for both ataxia-telangiectasia mutated ( Atm ) — which is involved in signalling the presence of DNA double-strand breaks and has a role in telomere maintenance — and telomerase RNA ( mTR ) — which maintains functional telomere length. Atm−/−mTR+/+ mice frequently have unrepaired breaks near the T-cell receptor loci, and consequently develop thymic lymphoma. Late generation Atm−/−mTR−/− mice have short telomeres and survive longer than Atm−/−mTR+/+ mice because of an increase in apoptosis and a decrease in thymic lymphoma. But what happens in early generation Atm−/−mTR−/− mice, in which short telomeres are not yet causing apoptosis, but DNA double-strand breaks are accumulating?

To the authors surprise, first generation Atm−/−mTR−/− mice also had increased survival compared with Atm−/−mTR+/+ mice, and they found that the mice developed less thymic lymphomas than expected. The authors ruled out increased apoptosis, decreased cell growth or proliferation as mechanisms for decreased tumour formation, suggesting that the phenotype was due to decreased tumour initiation, not decreased tumour growth. Telomere length decreased and the number of telomere-signal-free ends of chromosomes — which signify increasing genomic instaility — increased in subsequent generations of Atm−/−mTR−/− mice. The total number of chromosome translocations was similar in Atm−/−mTR+/+ and Atm−/−mTR−/− mice, but 15–25% of chromosomes in the tumours of Atm−/−mTR−/− mice had internal telomere signals at translocation junctions. The defining factor was that the number of translocation events involving the T-cell receptor loci were higher in first-generation Atm−/−mTR−/− mice, and many of these translocations contained telomeres at the translocation junctions.

So in this model, short dysfunctional telomeres readily fuse with DNA breaks, and this fusion competes with the formation of oncogenic translocations, and therefore decreases tumour initiation. In later generations, the higher rate of telomere dysfunction and increased genomic instability overrides the protective effect of telomere fusion to translocation sites. These findings might be particularly relevant in the development of human tumours in which a lack of DNA-repair pathways have a role.