This partially denatured hairpin substrate allowed the testing of both unwinding and rewinding activities. Note that in this design, the applied force destabilized the DNA duplex and therefore assisted unwinding but hindered rewinding. After enzyme dissociation, the spontaneous force-induced DNA unzipping was observed as a sudden and rapid recovery of the initial molecular extension.
The conversion of changes in molecular extension to number of bps rewound was performed by measuring the elastic response of ssDNA Supplementary Fig.
The force generated by these molecular motors during the DNA-rewinding process or robustness was investigated by examining the rewinding activity of UvsW and RecG over a wide range of applied forces using OT. Consequently, in this OT-passive configuration, the opposing applied force increased as DNA rewinding proceeded, allowing for testing the stalling behaviour of the motor 23 , By using the previously measured elasticity of ssDNA, we computed the rewinding rate as a function of the opposing force see Methods.
However, the enzyme processivities were strongly dependent on the force Supplementary Fig. Rates at high forces are computed as described in Methods both from OT-passive data Fig. S3 , purple crosses. Error bars are s. Helicase domains are marked in yellow, whereas the protein region that makes contact with the fork is shown in blue for example, wedge domain of RecG. Even though partially denatured hairpins are substrates for testing both rewinding and unwinding activities Figs 1a and 2a , RecG and UvsW only catalysed DNA hairpin rewinding but not unwinding Figs.
However, both RecG and UvsW were able to couple rewinding to unwinding in regressing forks. Addition of UvsW or RecG and ATP promoted fork regression via unwinding of the oligonucleotide concomitant with rewinding of the hairpin, although hairpin unwinding was never observed Supplementary Fig.
S4d , supporting the idea that these enzymes only perform efficient unwinding when coupled to rewinding. After the displacement of the bound oligonucleotide, the rewinding of the hairpin proceeded at a constant rate. In these conditions, rewinding is limited by the enzyme translocation, which necessarily implies an interaction between the helicase and at least one of the fork tails, inhibiting the instantaneous reformation of the hairpin expected below the refolding force.
This rewinding rate at low forces then corresponds to the maximum translocation rate of the enzyme Fig. Slow DNA rewinding limited by enzyme motion had been observed in single-molecule studies of the ssDNA translocation activity of several helicases 26 , 27 , Mechanical manipulation is a powerful tool to investigate the mechanisms of molecular motors 29 , In particular, the study of DNA unwinding by helicases assisted by mechanical forces has allowed the discrimination between passive and active mechanisms 26 , 27 , 31 , A similar analysis can be carried out for rewinding enzymes by measuring the reaction rate against the applied opposing forces.
Remarkably, when normalized to the translocation rate measured as the rewinding rate at low forces , both enzymes presented the same dependence on the applied force Fig. We extended the model proposed by Betterton et al. The proposed model is depicted in Fig. The extent of the slowing depends on the ability of the enzyme to stabilize the DNA duplex.
S5 , revealing their strong active character. The active and passive models tested here are analogous to the active disruption model and the Brownian ratchet model proposed for hexameric branch migration helicases The former can be directly measured from the ssDNA elasticity and the latter can be estimated from thermal or force denaturation data Supplementary Fig. Next, we investigated the ability of RecG and UvsW to regress forks with either lagging or leading nascent strands using MT.
In these assays, DNA forks were generated with a mer oligonucleotide, which mimics the nascent strand, hybridized to either the leading or the lagging strand and using force modulation Fig.
Addition of UvsW or RecG and ATP lead to the recovery of the formed hairpin in two phases: first, fork regression via simultaneous rewinding of the hairpin and displacing of the hybridized oligonucleotide, second, final hairpin rewinding after oligonucleotide departure. By repeating the force modulation in the presence of oligonucleotides and enzyme, oligonucleotide hybridization and fork regression could be cycled in a single experiment Fig.
Even though both enzymes translocate on ssDNA 38 , 39 , we found that excess oligonucleotide inhibited fork binding of UvsW only.
Consequently, the cyclic fork-regression assays for UvsW required sequential injections of oligonucleotide and enzyme separately, whereas RecG and oligonucleotide could be added simultaneously. These results demonstrate that RecG binds to model fork structures with very high affinity relative to ssDNA The molecular extensions corresponding to the initially formed hairpin, the totally denatured substrate and the partially denatured hairpin are highlighted in dark blue, light blue and pink, respectively.
For RecG, a single injection of oligonucleotide and enzyme is sufficient, whereas for UvsW measurements three separate injections are needed: first oligonucleotide injection, second buffer injection and third UvsW injection. Error bars are inversely proportional to the square root of the number of points for each bin. Previous studies on RecG, employing forks with heterologous arms to prevent spontaneous branch migration, demonstrated a preferential unwinding of forks with lagging nascent strand 4 , Here we investigated the preference of these enzymes for a special fork geometry using homologous junctions whose structures could be maintained by the applied force.
Under these conditions, we compared the time required for the initiation of the fork regression that reflects the protein-binding time t on with different fork geometries, measured from the cyclic fork-regression assay. The analysis shows that RecG binds ten-fold faster to forks with lagging nascent strand than to forks with leading nascent strand Fig.
In contrast, UvsW bound with a similar rate to either fork substrate Fig. S7c , in agreement with DNA footprinting results We recently developed an assay to generate a DNA substrate mimicking a stalled fork in situ , which allowed us to monitor UvsW-dependent Holliday junction HJ formation and its subsequent branch migration in real time This study revealed that UvsW frequently switches the direction of branch migration between fork regression and fork reversal—a property that turns out to be crucial for remodelling stalled replication forks leading to the resumption of DNA replication 17 , Here we performed HJ generation and migration assays with a stalled fork substrate with nt long nascent strands, Fig.
Fork regression and reversal were followed by monitoring Z e t Fig. The initial transient decrease in Z e corresponded to the formation and migration of the HJ, until the fork had been partially or totally regressed.
The subsequent increase in Z e corresponded to the migration of the HJ towards fork reversal. Note that, in our experimental configuration, the application of the force at the extremities of the fork favoured reversal over regression.
Therefore, spontaneous fork reversal occurred whenever the enzyme dissociated from the DNA Fig. The rates of RecG- and UvsW-catalysed branch migration during fork regression and fork reversal were mostly independent of the applied force and close to the enzyme-catalysed rates of DNA rewinding Supplementary Fig.
The switches in the HJ branch-migration direction were independent of the enzyme concentration Fig. This phenomenon might be related to changes in the HJ conformation controlled by the divalent metal ion concentration 43 , 44 ; the open and stacked-X HJ conformations favoured at low and high divalent ion concentrations, respectively, might facilitate and hinder the enzyme strand switching at the junction Fig.
The molecular extensions corresponding to the initial stalled fork and the final fully regressed configurations are highlighted in light blue and pink, respectively.
The average number of switches remains constant when changing the enzyme concentration from 0. S9 17 , 46 —two endergonic reactions. Our assays with a stalled fork substrate or substrates coated with ssDNA-binding protein Fig.
The active mechanism for fork regression is in stark contrast to the passive or Brownian ratchet model proposed for hexameric branch-migration helicases 37 , such as RuvAB, or DnaB 49 , 50 , in which the enzyme uses unidirectional motion to trap spontaneous bp fraying. This difference might arise from the role of the protein domain located at the DNA junction in RecG-like helicases so-called wedge domain 18 , which is not present in the case of hexameric helicases Therefore, we conclude that the mechanisms used for monomeric RecG-like helicases and hexameric helicases during rewinding and fork regression are different.
Our results showing that UvsW rewinds hairpins against denaturing forces Figs 1 and 2 imply simultaneous translocation of the enzyme on both strands of DNA and are inconsistent with such a model. Indeed, experiments performed with DNA substrates with regions of reverse backbone polarity Supplementary Fig. S7 demonstrated the importance of interactions between UvsW, the parental duplex DNA and both fork tails.
Moreover, we found that the interactions of these proteins with the parental duplex DNA are more pronounced with the lagging strand tail, supporting a rewinding mechanism based on the fork-regression model proposed by Singleton et al. The fact that such a scheme applies to two enzymes with low structural homology suggests that this might be a general mechanism for monomeric SF2 family-rewinding motors. One of the main roles associated with both RecG and UvsW enzymes is the rescue of stalled DNA replication forks via fork regression 13 , 14 , 15 , Here we demonstrate that both enzymes catalyse a set of reactions relevant to stalled DNA-replication fork rescue.
First, both helicases efficiently catalyse coupled DNA unwinding and rewinding. These activities are used to regress a fork away from the site of DNA damage. Second, once the forks have been regressed into a HJ structure, each helicase is capable of driving branch migration. Third, the enzymes display the ability to switch the direction of HJ branch migration and to restore the fork to its initial configuration Figs 5 and 6.
Our enzyme-concentration analysis indicates that the RecG- and UvsW-catalysed switches in HJ branch-migration direction are mediated by a single-enzyme complex, probably via a strand-switching mechanism High concentration of divalent ions, which is known to induce the transition from the open to the X-stacked HJ conformation 43 , 44 , inhibits the switching behaviour for both RecG and UvsW, showing that this reaction is very sensitive to the DNA structure at the junction.
Our recent findings showed that UvsW in collaboration with the T4 holoenzyme was able to overcome a DNA lesion by regressing the stalled forks and bypassing the lesion via a template-switching pathway The observed analogous activities of both these enzymes strongly suggest that RecG could also have the same role in E.
We also found that RecG binds preferentially to forks with a lagging nascent strand Fig. This binding specificity might allow RecG to efficiently target asymmetric forks for remodelling by promoting either lesion bypass or lesion excision repair 42 , In contrast, UvsW binds with similar affinity to different DNA substrates, which might confer a wider functional diversity necessitated by the rapid phage life cycle.
However, increasing evidence suggests that some helicases can rewind, or anneal, complementary strands of polynucleic acids in the presence or absence of nucleoside triphosphate Figure 1. Moreover, two so-called human helicases that were identified recently appear to only have ATP-dependent rewinding activity [ 11 — 15 ]. These discoveries not only enrich the definition of helicases but also establish the presence of a new type of protein: annealing helicase.
The mechanism of this novel strand annealing activity and its biological consequences remain largely unknown. In this paper, I will provide a brief overview of strand annealing activity found in various proteins across species and then focus on annealing helicases in humans and their potential mechanisms and functions. Most knowledge regarding the strand annealing activity of proteins has come from studies of model systems, including bacteria, yeast, and Xenopus laevis. The Lehman lab reported the ATP-dependent annealing activity of purified recombinant Escherichia coli RecA protein three decades ago [ 16 ].
Although similar results were obtained by several other labs [ 17 — 19 ], the annealing activity of RecA the human RAD51 homolog is likely due to the binding of single-stranded DNA ssDNA , which forms a nucleoprotein filament. The DNA replication polymerase Dpo1 of Sulfolobus solfataricus also possesses strand annealing activity [ 22 ].
Another yeast protein, Rad59, also stimulates complementary ssDNA annealing [ 27 , 28 ]. Interestingly, strand annealing activity has also been reported for some viral proteins. Several mammalian proteins have been found to possess annealing activity.
The annealing activity is restored by dephosphorylation of hnRNP by phosphatase 2A [ 34 , 35 ]. Human Mre11 complex mediates the annealing of complementary ssDNA molecules [ 38 ]. In summary, at least a dozen proteins, particularly those involved in DNA replication and repair, have been demonstrated to possess strand annealing activity.
However, it is surprising to find that helicases, which unwind double stranded DNA or RNA, also possess strand annealing activity. The annealing activity was first reported in RNA helicases Table 1. In , the Stahl lab discovered that RNA helicase p68 and its close relative p72 possess RNA annealing activity for two complementary RNA strands [ 41 ], and they also showed that Ddx42p, another p68 homolog, has similar activity [ 42 ].
The Lambowitz lab found that Mssp of S. This was the first demonstration of a DNA helicase with an intrinsic DNA annealing function residing in a separate domain of the same polypeptide Figure 2. Subsequently, many helicases, particularly RecQ family helicases, have been found to possess annealing activity. A single nucleotide polymorphism in RECQ1 correlates with decreased survival of pancreatic cancer patients [ 62 , 63 ].
The WRN helicase was reported to contain strand pairing activity [ 51 ], and the annealing activity was mapped to the C-terminal region aa — [ 52 ]. Later, the Vindigni lab reported that RECQ1 efficiently promotes strand annealing as a higher order oligomer pentamer or hexamer , while smaller oligomeric states dimer or monomer act to unwind duplex DNA [ 50 ]. Because of its robust annealing activity, the presence of a third strand e.
The purified recombinant human PIF1 proteins display robust annealing activity without ATP, and this activity resides in the N-terminal region aa 1— of the protein [ 56 ] Figure 2. Dna2 is a helicase and nuclease involved in Okazaki fragment processing, double-strand break DSB repair, telomere regulation, and mitochondrial function [ 72 ]. Both yeast and human DNA2 protein contain strand annealing properties.
Mutations in CSB gene cause Cockayne syndrome, a rare inherited genetic disorder characterized by UV sensitivity, severe neurological abnormalities, and progeroid symptoms [ 73 ]. The majority of SIOD patients have T-cell deficiency and associated risk for opportunistic infection, a common cause of death.
Loss of HARP affects cellular proliferation and differentiation, and the response to replication stress [ 79 ]. It was proposed that HARP might dictate its role in the S-phase-specific DNA damage response to protect stalled replication forks by minimizing the accumulation of ssDNA regions and facilitating the repair of collapsed replication forks [ 11 — 13 , 80 ].
More recently, the Cortez lab reported that the first HP domain is not required for annealing activity, and, intriguingly, HARP is able to catalyze branch migration of Holliday junctions HJs and regression of replication forks [ 83 ]. After discovering the unique activity of the HARP protein, the Kadonaga lab identified another annealing helicase that they named annealing helicase 2 AH2 [ 15 ]. In addition, AH2 contains an HNH motif at its extreme C-terminus Figure 2 , which is common in prokaryotes and is often associated with nuclease activity [ 85 ].
Contrary to expectations, the purified recombinant AH2 protein does not exhibit nuclease activity [ 15 ]. With no disease linked to AH2 or genetic model generated for AH2, the biological function of AH2 remains largely unknown.
Specific helicases need to function on the appropriate nucleic acid substrate at the appropriate time. A key emerging question is how these two opposite activities of helicase are precisely regulated.
Helicase is characterized by conserved helicase motifs. Some helicases also contain accessory domain s at the N- or C-terminus, such as nuclease domain and various protein-protein interaction domains. As shown in Figure 2 , studies of human BLM helicase and its orthologs including budding yeast Sgs1 and Drosophila BLM revealed that its N-terminal region contains strand annealing activity [ 64 ].
The annealing activity of PIF1 resides in its N-terminal domain [ 56 ]. Furthermore, studies of RECQ4 protein revealed that some missense mutants lose unwinding activity but still possess strand annealing activity [ 54 ]. These results suggest that the DNA unwinding and strand annealing activities can be uncoupled, but the question remains whether there is a conserved domain that controls annealing activity.
Although HP domain-like amino acids are found in the AH2, it is unlikely that the HP domain is a universal element that governs annealing activity across helicases. For example, the N-terminal region residue 1—56 of RECQ1 [ 88 ] and the C-terminal region aa — of the WRN helicase [ 52 ] are required for their respective annealing activities. Thus, it is unlikely that a single conserved domain is responsible for the annealing activity of these helicases.
More conclusive data will be obtained when more annealing helicases are identified. Certain helicases may self-assemble to form dimers or higher order oligomers, and this can influence their catalytic activity or biological function [ 1 — 3 ]. Thus, oligomerization might be important for the regulation of helicase annealing activity. Human RECQ1 helicase efficiently promotes strand annealing as a higher order oligomer tetramer while smaller oligomeric states dimer or monomer acting to separate duplex DNA [ 50 , 88 ].
Electron microscopy reconstructions of the higher order oligomeric form revealed that a cage-like structure forms a hollow channel, which may facilitate the annealing activity of RECQ1 [ 50 ]. These findings raise the possibility that higher order oligomers promote annealing activity and smaller order oligomers promote unwinding activity.
Nevertheless, additional studies are needed to address the relationship between the oligomerization and dual activities of helicases.
For helicases that possess unwinding activity, it makes sense that ATP fuels the unwinding activity, in turn, inhibits the annealing activity. However, for helicases with no detectable unwinding activity, it is largely unknown how ATP regulates their annealing activity.
Rather than fueling the unwinding activity by hydrolyzing ATP, ATP binding might cause a conformational change in the helicase that prevents annealing. If ATP indeed functions as a switch to regulate or balance the unwinding and rewinding activity of helicases, a promising avenue for future research will be to investigate the regulation mechanism, for example, structural determination of helicases with and without ATP.
RPA is a fundamental protein involved in all aspects of cellular metabolism see review [ 90 , 91 ]. In DNA repair processes, RPA physically coats ssDNA to protect it from degradation by nucleases and also serves as a scaffold protein to recruit other repair proteins e. RPA depletion causes a dramatic reduction in the formation of the annealing products in Xenopus egg extracts, suggesting that RPA is required for single-strand annealing [ 97 ]. In addition to RPA, several other proteins have been shown to promote annealing activity of helicases.
WRN is acetylated by the acetyltransferase p [ ]. Thus, helicase function may in specific cases be regulated by post translational modification through modulation of its strand annealing activity. Nevertheless, it remains largely unknown how annealing activity is modulated by these protein modifications. The biological function of so-called real helicases, which possess unwinding activity that includes RecQ family helicases [ 4 , 6 ], Pif1 [ 71 ], and Dna2 [ 72 ], has been extensively reviewed.
The focus here is on annealing activity of helicases. The physiological relevance of helicase annealing activity is revealed by the finding that several mutations observed in SIOD patients result in defective annealing activity in HARP protein [ 14 , 78 , ]. Although a limited number of annealing helicases have been identified, several biological functions have been indicated by related experimental evidence.
Stalled replication forks can arise during normal chromosome replication or in the presence of DNA lesions, but will collapse if being left unrepaired due to the presence of long stretches of ssDNA. HARP and AH2 might dictate their role in protecting stalled replication forks by minimizing the accumulation of ssDNA regions and facilitating the repair of collapsed replication forks during DNA replication [ ].
DNA fibre analyses show that restart of replication forks after 2 hours of aphidicolin treatment is reduced in HARP-depleted cells [ 11 , 81 ]. These data suggest that HARP promotes fork stability and restart by reannealing long stretches of ssDNA generated at stalled replication forks.
Indeed, very recently, the Cortez lab demonstrated that in vitro HARP can bind and branch-migrate three-way and four-way DNA structures, and catalyze extensive fork regression of model replication forks [ 83 ]. The RecQ family helicases have been well recognized to function in damaged replication forks [ ].
WRN- deficient cells are hypersensitive to replication blocking agents, including HU [ , ] and DNA-interstrand cross-linking drugs [ ].
In addition, it has been reported that both BLM and WRN are recruited to blocked replication forks in vivo [ ] and can catalyze fork regression in vitro [ , ]. Moreover, the Orren lab recently demonstrated that WRN and BLM reestablish functional replication forks to overcome fork blockage [ ]. However, it remains unknown how these helicases exert their annealing activity to contribute to replication fork restart. In addition to the RecQ helicases, human Pif1 helicase specifically recognizes and unwinds DNA structures resembling putative stalled replication forks [ 66 ].
Using yeast ribosomal DNA as a DNA replication model, it has been shown that the events of replication fork block are increased in Dna2 mutants [ ]. In particular, Dna2 is involved in Okazaki fragment processing [ 72 ], and it will be of interest to determine if its annealing activity stabilizes the lagging strand. The Pif1 helicase plays critical roles in both nuclear and mitochondrial genome stability [ 71 ].
Taken together, evidence suggested that annealing helicases are involved in DNA repair, but the question remains how the annealing activity contributes to DNA repair processes. Both crossover and noncrossover HR pathways are initiated by Rad51 that searches and invades base-paired strands of homologous DNA molecules, then D-loop and HJs are formed consequently Figure 3 b , left.
RecQ helicases have strand exchange activity [ 51 , ] and HJs branch migration ability [ , ]. SDSA is a mechanism in which homology-mediated repair of DSBs occurs without formation and resolution of ligated HJs; it anneals the newly synthesized strand with the single strand resulting from resection of the second end Figure 3 b , left.
Besides their function in DNA replication and repair, another function of annealing helicases might be in DNA transcription Figure 3 c.
Cas3 is a superfamily 2 helicase that possesses ATPase, helicase, and nuclease activities as evident in the Cas3 protein of Streptococcus thermophilus [ ].
Recently, the E. It remains unknown whether such annealing helicase is present in human. Helicases Dna2 and Pif1 have also been implicated in chromosome end stability [ ].
The purified recombinant PIF1 proteins bind telomeric DNA with a fold higher affinity compared to random sequence, and telomere shortening was observed when PIF1 was overexpressed [ ]. Telomere effects of Dna2 proteins have been reported in S. It will be of interest to know how these helicases exert their strand annealing activity, in particular RECQ4 that has robust annealing activity, to function in telomere maintenance.
Annealing helicases might participate in telomere metabolism, where single strand overhang could require an annealing helicase to form a more stable structure, such as T-loop Figure 3 d. Coordination of strand annealing and unwinding activity at the G-rich telomeric end may influence telomere stability by affecting DNA replication and repair processes, such as resolving G4 DNA. The characteristic feature of this class of enzymes is that they contain a conserved ATPase domain with the seven classic helicase-related motifs.
CHD7, a helicase domain containing Snf2 protein accounted for the majority of CHARGE syndrome, plays a role in transcription regulation by chromatin remodeling [ ]. Interestingly, most of the patient mutations are located in the helicase domain, suggesting its importance for their function.
However, it remains unknown whether they have strand annealing activity in vitro. The discovery of annealing helicases establishes the presence of a class of enzymes that possess only rewinding activity and opens a new area of research.
The range of proteins that function as annealing helicases remains to be determined. Researchers now hope to determine the biological function of HARP and AH2 more fully, as well as to discover more of these types of enzymes. There is no doubt that more and more annealing helicases will be identified. The coordinated action of unwinding and annealing may play a role in fork regression or synthesis-dependent strand annealing, in the pathway for DSB repair, as well as in transcription and telomere metabolism.
The challenge will then be to understand how cells regulate helicase unwinding and rewinding activity in vivo , and determine where or when the annealing activity of helicase is needed.
From an experimental standpoint, it would be great interest to identify and characterize separation of function mutants which: 1 inactivate helicase activity but retain strand annealing; 2 inactivate strand annealing but retain helicase activity. Finally, a better understanding of the biological function of annealing helicases is likely to provide the basis for treating a variety of human disorders, such as SIOD of HARP, premature aging of RecQ helicases, and cancers.
The author would like to thank Drs. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview.
Special Issues. Academic Editor: Grigory Dianov. Received 12 Apr Accepted 28 May Published 19 Jul Introduction Helicases are molecular motors that couple the energy of nucleoside triphosphate hydrolysis to the unwinding and remodeling of structured DNA or RNA [ 1 — 3 ]. Figure 1. A model of helicase function to unwind or rewind double-stranded nucleic acid. Note that helicase oval represents both translocation polarities; either ATP-dependent or ATP-independent for strand annealing activity has been observed in helicases see Table 1.
Table 1. Figure 2. Alignment of human DNA helicases that contain annealing activity. The annealing domain is indicated in yellow and the conserved helicase core domain in green; the conserved seven helicase motifs and the accessory domains are indicated. The total number of amino acids in each helicase protein is shown to the right.
Figure 3. The replication fork proceeds until the DNA damage is repaired or bypassed. Annealing helicases might participate in homologous recombination repair through double Holliday junction dHJ or synthesis-dependent strand annealing SDSA pathways left or microhomology-mediated end joining MMEJ or single strand annealing SSA pathways right. Noncrossover uncommon of dHJ is not shown. Model is adapted by analogy from one proposed for E. Annealing helicases may catalyze the formation of T-loop structure or sister chromatid exchange and homologous recombination-dependent DNA replication in ALT cells.
See text for details. References T. Lohman and K. Skip to main content Skip to navigation. Healing helicase stitches up DNA bubbles.
Manisha Lalloo Enjoy this story? References Science, DOI: No comments yet. You're not signed in. Eukaryotic Genome Complexity. RNA Functions. Pray, Ph. Citation: Pray, L. Nature Education 1 1 Arthur Kornberg compared DNA to a tape recording of instructions that can be copied over and over. How do cells make these near-perfect copies, and does the process ever vary? Aa Aa Aa. Initiation and Unwinding. Primer Synthesis. The Challenges of Eukaryotic Replication.
References and Recommended Reading Annunziato, A. Journal of Biological Chemistry , — Bessman, M. Journal of Biological Chemistry , — Kornberg, A. Science , — Lehman, I.
Journal of Biological Chemistry , — Losick, R. Science , — Mackiewicz, P. Nucleic Acids Research 32 , — Ogawa, T. Molecular and General Genetics , — Okazaki, R. Article History Close. Share Cancel.
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