Effect of loop length variation on quadruplex-Watson Crick duplex competition

Kumar, Niti; Sahoo, Bankanidhi; Varun, K. A. S.; Maiti, Sudipta; Maiti, Souvik

doi:10.1093/nar/gkn402

Cited by 62 publications

(67 citation statements)

References 59 publications

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“…It is well established that the folding motif for any DNA intramolecular quadruplex is highly regulated by the types of loops present [15][16][17][18][19][20]. The types of loops present will determine: 1) the syn or anti conformations of the guanine bases; 2) the strand orientations (i.e., parallel, antiparallel or mixed parallel-antiparallel); and 3) the orientation of the hydrogen bonds within one G-tetrad relative to the G-tetrad above and below [21].…”

Section: Duplexmentioning

confidence: 99%

A single base permutation in any loop of a folded intramolecular quadruplex influences its structure and stability

Yadav¹,

Sheardy²

2012

JBPC

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The human telomere sequence (TTAGGG) 4 folds into an unusual conformation possessing three G-tetrads linked by TTA loops. The first loop is a propeller loop while the second and third loops are transverse loops. Using Circular Dichroism (CD) spectroscopy, we have investigated the effect of sequence context on the structures and stabilities of intramolecular G-quadruplexes related to the human telomere sequence by considering all permutations of T and A within the loops. The results indicate that changing only one base in any one loop can have a dramatic effect on the conformation of the quadruplex as well as its melting temperature, T m . Thus, each sequence studied has a unique CD spectrum and T m . In general, variants with a modified second loop are the most stable while the wild type sequence is the least stable. The observed difference in CD spectra and melting temperature are discussed in terms of base stacking within the loop and stacking of the loop bases with adjacent G-tetrads.

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Section: Duplexmentioning

confidence: 99%

A single base permutation in any loop of a folded intramolecular quadruplex influences its structure and stability

Yadav¹,

Sheardy²

2012

JBPC

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“…Recent studies have shown that human telomeres form GQ structures in vivo (12,13) and in cell extracts (14). At physiologically relevant ionic conditions (∼150 mM K + ), GQs are thermodynamically more stable than competing Watson-Crick pairing (15). These structures were often regarded as obstacles for recruitment of telomerase (16) and translocation of the DNA replication machinery (17), and their unfolding requires helicase activity (17)(18)(19) or ssDNA binding proteins (20,21).…”

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confidence: 99%

G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding

Ray

Bandaria

Qureshi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

143

144

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Human telomeres terminate with a single-stranded 3′ G overhang, which can be recognized as a DNA damage site by replication protein A (RPA). The protection of telomeres (POT1)/POT1-interacting protein 1 (TPP1) heterodimer binds specifically to single-stranded telomeric DNA (ssTEL) and protects G overhangs against RPA binding. The G overhang spontaneously folds into various G-quadruplex (GQ) conformations. It remains unclear whether GQ formation affects the ability of POT1/TPP1 to compete against RPA to access ssTEL. Using single-molecule Förster resonance energy transfer, we showed that POT1 stably loads to a minimal DNA sequence adjacent to a folded GQ. At 150 mM K + , POT1 loading unfolds the antiparallel GQ, as the parallel conformation remains folded. POT1/TPP1 loading blocks RPA's access to both folded and unfolded telomeres by two orders of magnitude. This protection is not observed at 150 mM Na + , in which ssTEL forms only a lessstable antiparallel GQ. These results suggest that GQ formation of telomeric overhangs may contribute to suppression of DNA damage signals.telomere protection | DNA damage response | single molecule imaging H uman telomeres consist of 2,000-30,000 bp of doublestranded TTAGGG repeats and terminate with a 50-to 200-nt-long, single-stranded 3′ G overhang (1). Telomeric termini need to be protected against DNA damage signals to ensure genome integrity. Replication protein A (RPA) nonspecifically binds ssDNA, is highly abundant in eukaryotes, and plays a role in DNA replication and repair (2). RPA binding to ssDNA, including telomeric overhangs, activates the ataxia telangiectasia and Rad3-related checkpoint (2, 3). The protection of telomeres (POT1)/telomere protection protein (TPP1) subunit of the shelterin complex contributes to telomere protection by specifically binding to the G overhang (4, 5). RPA is 1,000-fold more abundant than POT1/TPP1 and has a similar affinity for singlestranded telomeric DNA (ssTEL) (6, 7). Therefore, POT1/TPP1 alone may not be able to effectively compete against RPA binding (8, 9). Efficient protection of ssTEL against RPA binding may require association of POT1/TPP1 to the rest of the shelterin complex along double-stranded telomeric tracts or other telomere-associated proteins (6, 9).Another potentially significant factor that could influence the competition between RPA and POT1/TPP1 is the ability of ssTEL to form G-quadruplex (GQ) structures (10, 11). Recent studies have shown that human telomeres form GQ structures in vivo (12, 13) and in cell extracts (14). At physiologically relevant ionic conditions (∼150 mM K + ), GQs are thermodynamically more stable than competing Watson-Crick pairing (15). These structures were often regarded as obstacles for recruitment of telomerase (16) and translocation of the DNA replication machinery (17), and their unfolding requires helicase activity (17-19) or ssDNA binding proteins (20,21). It remains unclear whether GQ formation of ssTEL plays any role in protection of telomeres. ssTEL sequences fold into parallel...

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“…These studies combined make telomere sequences prime subjects for direct-effect IR damage which is why in future experiments we would like to generate DNA substrates that simulate in vivo telomeric DNA. These would include double-stranded telomeric DNA and the highly stable G-quadruplex structures within the single-stranded G-rich overhang (Biffi et al 2013; Gomez et al 2006; Hänsel et al 2013; Kumar et al 2008; Lam et al 2013; Sen et al 1988; Wu et al 2008; Paeschke 2005; Paeschke et al 2008). …”

Section: Discussionmentioning

confidence: 99%

Radioresistance of GGG sequences to prompt strand break formation from direct-type radiation damage

Black

Miller

Hayes

2016

Radiat Environ Biophys

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Purpose As humans, we are constantly exposed to ionizing radiation from natural, man-made and cosmic sources which can damage DNA, leading to deleterious effects including cancer incidence. In this work we introduce a method to monitor strand breaks resulting from damage due to the direct effect of ionizing radiation and provide evidence for sequence-dependent effects leading to strand breaks. Materials and methods To analyze only DNA strand breaks caused by radiation damage due to the direct effect of ionizing radiation, we combined an established technique to generate dehydrated DNA samples with a technique to analyze single strand breaks on short oligonucleotide sequences via denaturing gel electrophoresis. Results We find that direct damage primarily results in a reduced number of strand breaks in guanine triplet regions (GGG) when compared to isolated guanine (G) bases with identical flanking base context. In addition, we observe strand break behavior possibly indicative of protection of guanine bases when flanked by pyrimidines, and sensitization of guanine to strand break when flanked by adenine (A) bases in both isolated G and GGG cases. Conclusions These observations provide insight into the strand break behavior in GGG regions damaged via the direct effect of ionizing radiation. In addition, this could be indicative of DNA sequences that are naturally more susceptible to strand break due to the direct effect of ionizing radiation.

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Effect of loop length variation on quadruplex-Watson Crick duplex competition

Cited by 62 publications

References 59 publications

A single base permutation in any loop of a folded intramolecular quadruplex influences its structure and stability

A single base permutation in any loop of a folded intramolecular quadruplex influences its structure and stability

G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding

Radioresistance of GGG sequences to prompt strand break formation from direct-type radiation damage

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