RecQ helicases: Multiple structures for multiple functions?

Vindigni, Alessandro; Hickson, Ian D.

doi:10.2976/1.3079540

Cited by 60 publications

(56 citation statements)

References 115 publications

(140 reference statements)

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“…The intermediate stimulation of hpol by WRN exonuclease and RQC domains is consistent with such a notion. Several studies have reported that WRN interacts with its binding partners through more than one domain (60). Indeed, a similar bipartite interaction between WRN and the Bloom syndrome protein (BLM) was shown previously and mapped to residues 50 -120 and 949 -1092 (61), strikingly similar to our results.…”

Section: Discussionsupporting

confidence: 91%

Enhancement of Human DNA Polymerase η Activity and Fidelity Is Dependent Upon a Bipartite Interaction with the Werner Syndrome Protein

Maddukuri

Ketkar

Eddy

et al. 2012

Journal of Biological Chemistry

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Background:The Werner syndrome protein (WRN) stimulates specialized Y-family DNA polymerase activity through an unknown mechanism. Results: A bipartite interaction between WRN and hpol increases the efficiency and fidelity of polymerization. Conclusion: Direct interactions between hpol and WRN increase k pol 4-fold and decrease the misinsertion frequency 2.5-to 4.5-fold. Significance: WRN-mediated enhancement of polymerase accuracy and efficiency may suppress mutations and genomic instability.

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Section: Discussionsupporting

confidence: 91%

Enhancement of Human DNA Polymerase η Activity and Fidelity Is Dependent Upon a Bipartite Interaction with the Werner Syndrome Protein

Maddukuri

Ketkar

Eddy

et al. 2012

Journal of Biological Chemistry

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“…The phenomenon that ssDNA translocation is performed by monomers and dsDNA unwinding is performed by oligomers was observed in the case of other SF1 and SF2 helicases, including PcrA (38), UvrD (34,(40)(41)(42), Rep (43,44), and NS3 (37), suggesting a role of oligomerization in the regulation of switching between different activities. Dynamic oligomerization was also reported for human WRN (45) and RecQ1 (46) helicases, suggesting the importance of substrate-induced oligomerization also in the case of RecQ-family helicases (47). Furthermore, oligomerization is likely to be influenced by solution conditions (e.g., temperature, ionic strength, pH).…”

Section: Discussionmentioning

confidence: 74%

RecQ helicase translocates along single-stranded DNA with a moderate processivity and tight mechanochemical coupling

Sarlós

Gyimesi

Kovács

2012

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

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Maintenance of genome integrity is the major biological role of RecQ-family helicases via their participation in homologous recombination (HR)-mediated DNA repair processes. RecQ helicases exert their functions by using the free energy of ATP hydrolysis for mechanical movement along DNA tracks (translocation). In addition to the importance of translocation per se in recombination processes, knowledge of its mechanism is necessary for the understanding of more complex translocation-based activities, including nucleoprotein displacement, strand separation (unwinding), and branch migration. Here, we report the key properties of the ssDNA translocation mechanism of Escherichia coli RecQ helicase, the prototype of the RecQ family. We monitored the presteady-state kinetics of ATP hydrolysis by RecQ and the dissociation of the enzyme from ssDNA during single-round translocation. We also gained information on the translocation mechanism from the ssDNA length dependence of the steady-state ssDNA-activated ATPase activity. We show that RecQ occludes 18 ± 2 nt on ssDNA during translocation. The hydrolysis of ATP is noncooperative in the presence of ssDNA, indicating that RecQ active sites work independently during translocation. In the applied conditions, the enzyme hydrolyzes 35 ± 4 ATP molecules per second during ssDNA translocation. RecQ translocates at a moderate processivity, with a mean run length of 100-320 nt on ssDNA. The determined tight mechanochemical coupling of 1.1 ± 0.2 ATP consumed per nucleotide traveled indicates an inchworm-type mechanism.H elicases are NTP-driven nucleic acid motors that couple the liberation of chemical energy to mechanical movement along nucleic acid strands to exert diverse biological activities. Escherichia coli RecQ helicase is the prototype of its family [belonging to superfamily (SF) 2], whose members are essential in genome maintenance from bacteria to humans (1-3) by playing roles in homologous recombination (HR)-mediated dsDNA break (DSB) repair (4-7). In humans, loss-of-function mutations of at least three RecQ helicase homologs are linked to diseases (mostly Bloom, Werner, and Rothmund-Thomson syndromes), which are generally characterized by genome instability resulting in cancer predisposition and premature aging (8). E. coli RecQ suppresses illegitimate recombination (9) and regulates HR-mediated DSB repair via initiating HR and processing HR intermediates (2). Moreover, RecQ stabilizes stalled replication forks as part of the RecF pathway (10, 11).Different types of translocation mechanisms were proposed for SF1 and SF2 helicases. An inchworm mechanism was proposed for bacterial PcrA (12, 13), UvrD (14), and human RecQfamily Bloom syndrome (BLM) (15) helicases, which perform unidirectional translocation based on the consumption of one ATP per kinetic cycle (dictated by a single rate-limiting step), leading to a single nucleotide translocation along ssDNA. A more complex, nonuniform inchworm stepping mechanism was suggested for UvrD (16), NS3 (17), and RecBCD (18) helicase...

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“…This sophisticated reaction is performed by the so-called "dissolvasome" complex composed of a specific RecQ helicase (BLM in humans/Sgs1 in budding yeast) and a type IA topoisomerase known as topoisomerase III ( Fig. 2; for general reviews about RecQ helicases and topoisomerases, see Champoux 2001;Wang 2002;Bachrati and Hickson 2003;Viard and de la Tour 2007;Chu and Hickson 2009;Vindigni and Hickson 2009. In this review, we first take a historical look at the experimental evidence that led some groups to formulate the proposal that a reaction akin to dissolution must exist, and which then led Wu and Hickson (2003) to confirm its existence by reconstitution of the dissolution reaction in vitro using purified proteins. Following that, we will review the individual and combined roles of the components of what we will term the dHJ dissolvasome.…”

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confidence: 99%