Telomerase is responsible for adding telomeric DNA repeats at the ends of chromosomes. However, not all cells that produce catalytically active telomerase are capable of telomerase-dependent telomere maintenance. This suggested to Wong et al. that telomerase might be regulated by access to its substrate, as they report in Nature Cell Biology.

The ribonucleoprotein (RNP) telomerase is a complex of protein and RNA that uses an integral RNA component as the template for telomere DNA synthesis by the inbuilt catalytic subunit, telomerase reverse transcriptase (TERT). Regulation occurs at the levels of both RNP accumulation and catalytic activation by RNP association with TERT. To investigate the possibility of a third level of regulation, the authors examined the subcellular localization of a green-fluorescent-protein–human-TERT (GFP–hTERT) fusion protein by confocal microscopy. Conditions were chosen so that hTERT production limited telomerase activation, to ensure maximum incorporation of GFP–hTERT into telomerase RNP complexes.

In fibroblast cells, GFP–hTERT generally showed preferential nucleolar association, although some cells showed a more diffuse distribution. When cells were synchronized, Collins and co-workers found that most cells in G1 phase showed prominent nucleolar fluorescence. By contrast, cells in late S/G2 phase had a more diffuse intranuclear telomerase distribution, coincident with the timing of telomere replication.

They then went on to study the impact of oncogenic transformation and DNA damage on the subnuclear localization of catalytically active telomerase. In tumour and transformed cells, telomerase was almost completely dissociated from nucleoli at all stages of the cell cycle. And introduction of the SV40 genome with the T-antigen oncogene into a primary cell line was enough to release telomerase from nucleoli into the nucleoplasm.

Exposure of both primary and transformed cells to ionizing radiation caused a pronounced relocalization of GFP–hTERT to the nucleoli. This suggests that removing telomerase from damaged DNA reduces the potential for inappropriate repair of DNA breaks by telomere synthesis. The obvious next step would be to study the molecular mechanisms that underlie this phenomenon of subnuclear telomerase shuttling.