The DNA structure and sequence preferences of WRN underlie its function in telomeric recombination events

Edwards, Deanna N.; Machwe, Amrita; Chen, Li; Bohr, Vilhelm A.; Orren, David K.

doi:10.1038/ncomms9331

Cited by 17 publications

(15 citation statements)

References 64 publications

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“…The most selective substrate specificity was seen in WRN, which interacted only with the telomeric GQ in the presence of ATP. This finding is consistent with the high telomeric specificity of WRN displayed in DNA deletion suppression (25,38) and unwinding activity (39).…”

Section: Discussionsupporting

confidence: 87%

Single-molecule imaging reveals a common mechanism shared by G-quadruplex–resolving helicases

Tippana

Hwang

Opresko

et al. 2016

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

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105

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G-quadruplex (GQ) is a four stranded DNA secondary structure that arises from a guanine rich sequence. Stable formation of GQ in genomic DNA can be counteracted by the resolving activity of specialized helicases including RNA helicase AU (associated with AU rich elements) (RHAU) (G4 resolvase 1), Bloom helicase (BLM), and Werner helicase (WRN). However, their substrate specificity and the mechanism involved in GQ unfolding remain uncertain. Here, we report that RHAU, BLM, and WRN exhibit distinct GQ conformation specificity, but use a common mechanism of repetitive unfolding that leads to disrupting GQ structure multiple times in succession. Such unfolding activity of RHAU leads to efficient annealing exclusively within the same DNA molecule. The same resolving activity is sufficient to dislodge a stably bound GQ ligand, including BRACO-19, NMM, and Phen-DC3. Our study demonstrates a plausible biological scheme where different helicases are delegated to resolve specific GQ structures by using a common repetitive unfolding mechanism that provides a robust resolving power.

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Section: Discussionsupporting

confidence: 87%

Single-molecule imaging reveals a common mechanism shared by G-quadruplex–resolving helicases

Tippana

Hwang

Opresko

et al. 2016

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

Self Cite

105

View full text Add to dashboard Cite

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“…It should also be noted that many other helicases are also known to affect telomerase. In humans, the BLM (47,48) and WRN (49,50) RecQ family helicases are both involved in telomere maintenance (reviewed in (51)). Similarly, the functional homolog of BLM in yeast, Sgs1, is linked to telomere maintenance, though usually in the context of recombination-mediated telomere lengthening in the absence of telomerase (52)(53)(54).…”

Section: Are Other Helicases Also Involved In Telomere Length Homeostmentioning

confidence: 99%

TheSaccharomyces cerevisiaeHrq1 and Pif1 DNA helicases synergistically modulate telomerase activityin vitro

Nickens

Rogers

Bochman

2018

Preprint

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Telomere length homeostasis is vital to maintaining genomic stability and is regulated by multiple factors, including telomerase activity and DNA helicases. The Saccharomyces cerevisiae Pif1 helicase was the first discovered catalytic inhibitor of telomerase, but recent experimental evidence suggests that Hrq1, the yeast homolog of the disease-linked human RecQ-like helicase 4 (RECQL4), plays a similar role via an undefined mechanism. Using yeast extracts enriched for telomerase activity and an in vitro primer extension assay, here we determined the effects of recombinant wild-type and inactive Hrq1 and Pif1 on total telomerase activity and telomerase processivity. We found that titrations of these helicases alone have equal-but-opposite biphasic effects on telomerase, with Hrq1 stimulating activity at high concentrations. When the helicases were combined in reactions, however, they synergistically inhibited or stimulated telomerase activity depending on which helicase was catalytically active. These results suggest that Hrq1 and Pif1 interact and that their concerted activities ensure proper telomere length homeostasis in vivo. We propose a model in which Hrq1 and Pif1 cooperatively contribute to telomere length homeostasis in yeast.

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“…It should also be noted that many other helicases are also known to affect telomerase. In humans, the BLM (47,48) and WRN (49,50) RecQ family helicases are both involved in telomere maintenance (51). Similarly, the functional homolog of BLM in yeast, Sgs1, is linked to telomere maintenance, although usually in the context of recombination-mediated telomere lengthening in the absence of telomerase (52-54).…”

Section: Are Other Helicases Also Involved In Telomere Length Homeostmentioning

confidence: 99%

The Saccharomyces cerevisiae Hrq1 and Pif1 DNA helicases synergistically modulate telomerase activity in vitro

Nickens

Rogers

Bochman

2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Telomere length homeostasis is vital for maintaining genomic stability and is regulated by multiple factors, including telomerase activity and DNA helicases. The Pif1 helicase was the first discovered catalytic inhibitor of telomerase, but recent experimental evidence suggests that Hrq1, the yeast homolog of the disease-linked human RecQ-like helicase 4 (RECQL4), plays a similar role via an undefined mechanism. Using yeast extracts enriched for telomerase activity and an primer extension assay, here we determined the effects of recombinant WT and inactive Hrq1 and Pif1 on total telomerase activity and telomerase processivity. We found that titrations of these helicases alone have equal-but-opposite biphasic effects on telomerase, with Hrq1 stimulating activity at high concentrations. When the helicases were combined in reactions, however, they synergistically inhibited or stimulated telomerase activity depending on which helicase was catalytically active. These results suggest that Hrq1 and Pif1 interact and that their concerted activities ensure proper telomere length homeostasis We propose a model in which Hrq1 and Pif1 cooperatively contribute to telomere length homeostasis in yeast.

show abstract

The DNA structure and sequence preferences of WRN underlie its function in telomeric recombination events

Cited by 17 publications

References 64 publications

Single-molecule imaging reveals a common mechanism shared by G-quadruplex–resolving helicases

Single-molecule imaging reveals a common mechanism shared by G-quadruplex–resolving helicases

TheSaccharomyces cerevisiaeHrq1 and Pif1 DNA helicases synergistically modulate telomerase activityin vitro

The Saccharomyces cerevisiae Hrq1 and Pif1 DNA helicases synergistically modulate telomerase activity in vitro

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