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A DNA-hairpin model for repeat-addition processivity in telomere synthesis

Abstract

We propose a DNA-hairpin model for the processivity of telomeric-repeat addition. Concomitantly with template-RNA translocation after each repeat synthesis, the complementary DNA repeat, for example, AGGGTT, loops out in a noncanonical base-paired hairpin, thus freeing the RNA template for the next round of repeat synthesis. The DNA hairpin is temporarily stabilized by telomerase and the incoming dGTP but becomes realigned for processive telomere synthesis.

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Figure 1: Telomerase.
Figure 2: Telomeric repeats.
Figure 3: The structural cavity and flexibility of TERT accommodate the DNA-hairpin loopout.
Figure 4: A DNA-hairpin model for repeat-addition processivity.

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Acknowledgements

We thank K. Collins for guiding us throughout the project, J.-L. Chen and T.R. Cech for insightful discussion, J.P. Cooper, T. de Lange, C.W. Greider, D. Rhodes and M.D. Stone for encouragement and D.J. Leahy and M. Gellert for critical reading of the manuscript. This work was funded by the US National Institutes of Health Intramural Program (DK036146-08 to W.Y.).

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Correspondence to Wei Yang.

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Supplementary information

Structural differences between p66 and p51 subunits of HIV-1 RT and unfolding of the β-linker.

After superposition of the palm domains in p51 and p66 (PDB 1RTD)29, the movement of the thumb (green) in the two subunits is morphed. The β-linker (pink) between the thumb and palm domain (made of three β-strands) is unfolded in the p51 subunit. (MOV 757 kb)

Animation of the DNA hairpin model.

At the end of each cycle of repeat addition, while the RNA template (dark red) and DNA primer (orange) hybrid is translocated together, the 3′ end of DNA remains in the active site of TERT (shown as an outlined pink oval), and one telomeric repeat, e.g. AGGGTT, is looped out. The underscored T, which is recognized by TRBD as a signal for pausing DNA hairpin formation, is highlighted in olive color. Binding of the incoming dGTP stabilizes the hairpin loopout and also promotes the DNA realignment for the next round of repeat synthesis. (MOV 1349 kb)

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Yang, W., Lee, YS. A DNA-hairpin model for repeat-addition processivity in telomere synthesis. Nat Struct Mol Biol 22, 844–847 (2015). https://doi.org/10.1038/nsmb.3098

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