Telomeric overhang length determines structural dynamics and accessibility to telomerase and ALT-associated proteins

Helen Hwang, Alex Kreig, Jacob Calvert, Justin Lormand, Yongho Kwon, James M. Daley, Patrick Sung, Patricia L. Opresko, Sua Myong

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)842-853
Number of pages12
JournalStructure
Volume22
Issue number6
DOIs
StatePublished - Jun 10 2014
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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