Frustrated folding of guanine quadruplexes in telomeric DNA

Abstract Human chromosomes terminate in long, single-stranded, DNA overhangs of the repetitive sequence (TTAGGG)n. Sets of four adjacent TTAGGG repeats can fold into guanine quadruplexes (GQ), four-stranded structures that are implicated in telomere maintenance and cell immortalization and are targe...

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Bibliographic Details
Published in:Nucleic acids research 2021-04, Vol.49 (6), p.3063-3076
Main Authors: Carrino, Simone, Hennecker, Christopher D, Murrieta, Ana C, Mittermaier, Anthony
Format: Article
Language:English
Subjects:
Chemical Biology and Nucleic Acid Chemistry
DNA - chemistry
G-Quadruplexes
Kinetics
Tandem Repeat Sequences
Telomere - chemistry
Thermodynamics
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Summary:Abstract Human chromosomes terminate in long, single-stranded, DNA overhangs of the repetitive sequence (TTAGGG)n. Sets of four adjacent TTAGGG repeats can fold into guanine quadruplexes (GQ), four-stranded structures that are implicated in telomere maintenance and cell immortalization and are targets in cancer therapy. Isolated GQs have been studied in detail, however much less is known about folding in long repeat sequences. Such chains adopt an enormous number of configurations containing various arrangements of GQs and unfolded gaps, leading to a highly frustrated energy landscape. To better understand this phenomenon, we used mutagenesis, thermal melting, and global analysis to determine stability, kinetic, and cooperativity parameters for GQ folding within chains containing 8–12 TTAGGG repeats. We then used these parameters to simulate the folding of 32-repeat chains, more representative of intact telomeres. We found that a combination of folding frustration and negative cooperativity between adjacent GQs increases TTAGGG unfolding by up to 40-fold, providing an abundance of unfolded gaps that are potential binding sites for telomeric proteins. This effect was most pronounced at the chain termini, which could promote telomere extension by telomerase. We conclude that folding frustration is an important and largely overlooked factor controlling the structure of telomeric DNA. Graphical Abstract Graphical Abstract Mutagenesis, thermal melts and computational analyses show that folding frustration is a key determinant of guanine quadruplex folding in long telomeric repeat DNA.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkab140