Structure
Volume 22, Issue 6, 10 June 2014, Pages 842-853
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Article
Telomeric Overhang Length Determines Structural Dynamics and Accessibility to Telomerase and ALT-Associated Proteins

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Highlights

  • Telomeric overhang exhibits dynamic behavior when greater than four TTAGGG repeats

  • Four and eight repeats yield low accessibility to WRN, BLM, Rad51, and telomerase

  • Five to seven repeats yield increased accessibility to loading of the same proteins

  • POT1 binds all repeat lengths proficiently, suggesting an active disruption of GQ

Summary

The G-rich single-stranded DNA at the 3′ end of human telomeres can self-fold into G-quaduplex (GQ). However, telomere lengthening by telomerase or the recombination-based alternative lengthening of telomere (ALT) mechanism requires protein loading on the overhang. Using single-molecule fluorescence spectroscopy, we discovered that lengthening the telomeric overhang also increased the rate of dynamic exchanges between structural conformations. Overhangs with five to seven TTAGGG repeats, compared with four repeats, showed much greater dynamics and accessibility to telomerase binding and activity and loading of the ALT-associated proteins RAD51, WRN, and BLM. Although the eight repeats are highly dynamic, they can fold into two GQs, which limited protein accessibility. In contrast, the telomere-specific protein POT1 is unique in that it binds independently of repeat number. Our results suggest that the telomeric overhang length and dynamics may contribute to the regulation of telomere extension via telomerase action and the ALT mechanism.

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