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Subtle alterations to the telomeric nucleotides have previously been shown to cause telomeric disruption in a cellular context (Fouquerel et al, 2021; Mender et al, 2021; Stefl et al, 2001). Even changes of only one atom in a nucleotide, including replacing an oxygen of a guanine with a sulfur to form therapeutic 6-thioguanine nucleotides or the adduction of an extra oxygen onto guanine to form 8-oxoguanine nucleotides, have significant biological consequences in the context of telomerase. Therefore, in order to prevent this telomeric disruption, the telomerase active site appears to have evolved a high degree of stringency towards noncanonical nucleotides, including both rNTPs and mismatched dNTPs. This stringency was evident by the reduced telomere elongation efficiency with every variant tested; other mutations could also be identified with this system that show increases in telomere elongation efficiency. Our structural characterization of the telomerase catalytic cycle allowed us to efficiently modify the stringent active site of telomerase, generating a human telomerase variant that readily inserts rNTPs. The applications shown here highlight the potential of combining model TERTs with complementary human telomerase studies to further probe the telomerase catalytic mechanism and screen future telomerase-targeting therapeutics.

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This said, while Tribolium TERT provides a good model system for studying TERT structure, it lacks the TEN domain and a large part of the IFD, which have been shown to be crucial for TERT activity and processivity in human and Tetrahymena. This major difference and whether the kinetics observations can be generalized to other telomerases warrants a discussion.

The reviewers and the reviewing editor agreed that this work is significant because it is not known how telomerase selects the correct nucleotide for insertion into the telomeric repeat from a pool of nucleotide with various sugars and base pairing properties. This work is an important advance defining (at least in vitro) nucleotide selection by telomerase through the first high resolution crystal structures of Triboliumcastaneum telomerase reverse transcriptase (TERT) throughout its catalytic cycle and characterization of the Tribolium and human TERT kinetics. The authors solved the three structures of Tribolium TERT in complex with a DNA/RNA duplex with 1 nucleotide (nt) overhang, the same duplex with a non-hydrolyzable analog of dGTP and a product DNA/RNA duplex. The most novel finding was a steric gate which allows TERT to discriminate dNTPs from rNTPs and the authors show that this residue (Y717) serves similar functions in human telomerase.

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The transition between these two states represents the nucleotide binding step, measured as a dissociation constant (Kd). If the resulting ternary complex (TERT:DNA:dNTP) is in the proper orientation, TERT will catalyze the formation of a phosphodiester bond and extend the telomere by one nucleotide (Figure 1A, state C1). The transition between these two states is the chemistry step, and its theoretical maximum rate with saturating nucleotide concentration is described as kpol.

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Please include the details of the telomerase used. Was a recombinant telomerase with 3xFLAG tag and overexpressed hTR used? This is important as we have now seen that the tags used for telomerase play a role for in-vitro and in-vivo activity.

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These values were 120 μM for the 6-nucleotide overhang, and 4, 31, and 5 μM for four, two, and single nucleotide overhangs, respectively. Of note, out of all six templating positions, the substrate with six templating bases exhibited altered kinetics compared to the other 5 positions.

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In response to this question, we refer the reviewers to a publication that examined the impact of ribonucleotides in the template for telomerase (Collins and Greider, 1995, EMBO). Briefly, telomerase primer extension assays were performed using primers containing various amounts of ribonucleotides present in the primer strand (see Figure 6 in the referenced work). As predicted by the reviewers, in some cases, placing ribonucleotides in the primer strand inhibited even the first extension of telomerase. In other cases, such as the oligonucleotide that only had three ribonucleotides present (sequence: d(G3T2G)2G3r(U2G) ), telomerase extended the substrate with a reduced efficiency. We feel that the insights from these hybrid substrates better inform our interpretation of how ribonucleotides influence the mechanism of telomerase.

This is the list of files that are part of this repo. Each file contains detailed comments/troubleshoot tips/corresponding figure/data identifier along with associated code.

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Y256A) for both (A) rGTP insertion and (B) dGTP insertion (Supplementary file 3, Table 3a). Error bars represent standard deviation of the mean.

The main concern of the reviewers was related to "state I" designation. The authors chose a substrate where the RNA primer has just one 3' nucleotide overhang, perhaps to prevent subsequent cycles of catalysis. But since tcTERT uses RNA primers with up to 6 nt overhang, it is conceivable that the template-TERT conformation, especially the RNA-interacting residues could be very different between 1 and 6 templating bases. In a natural telomerase RNP, the RNA template threads through the TERT ring. The reviewers questioned whether "state I" described in the paper with only 1 nt overhang truly represents state I. In the recent Tetrahymena EM structure at 4/8 Å (Jiang et al, Science 2021), a stretch of the locked-DNA substrate is bound to the RNA template, which may be more representative of state I in the cycle. For the main conclusions of this paper to be valid, the authors need to provide a new structure of state I with the 6 nt overhang RNA primer (preferred) or show that the structure they have behaves the same way as State I.

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Prior to crystallization, we complexed tcTERT with its nucleic acid substrate by mixing them at a 1:1/2 ratio of protein to DNA. To increase protein solubility, we included 520 mM KCl when preparing to mix tcTERT with its nucleic acid substrate. We then used sitting drop vapor diffusion to grow binary complex crystals in conditions containing 11% isopropanol, 0/1 M KCl, 25 mM MgCl2, and 50 mM sodium cacodylate pH 6/5. Volume ratios for the optimal crystal growth were optimized to 2/3 µL tcTERT binary complex crystals + 1/7 µL of our crystallization condition, to make 4 µL total. For the ternary complex crystals, we used the same conditions, but included 0/69 mM dGpCpp (Jena Biosciences), the next matched incoming nucleotide in the sequence. Finally, for the product complex, we formed a DNA strand one nucleotide longer by incubating 2/5 mM dGTP with tcTERT and its nucleic acid substrate, allowing the reaction to occur at 22°C for 30 min prior to setting up crystallization drops. In all cases, crystals were transferred to a cryosolution containing 80% reservoir solution and 20% 2-methyl-2,4-pentanediol by volume before flash cooling them in liquid nitrogen.

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For the mismatched insertion, the kpol decreased 129-fold to 0/0081 s−1 and the Kd increased 76-fold to 1/3 mM (Figure 3E). The resulting catalytic efficiencies (kpol/Kd) for a matched versus mismatched nucleotide insertion indicate telomerase will insert the wrong nucleotide ~1 in 10,000 nucleotide insertion events. This places telomerase at a moderate fidelity of base selection compared to other DNA polymerases (Figure 3G). For rNTP discrimination, the kpol for inserting a rGTP decreased 281-fold to 0/0037 s−1 and the Kd increased 49-fold to 0/89 mM (Figure 3F).

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Also the authors should elaborate more on the TR version for T. casteneum. We assume as readers that the authors could not co-crystalize with "tcTR" for similar reasons as the field is not able to crystalize human hTR + hTERT. Please provide some background on that (perhaps in the Introduction).

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We thank Jay Nix (Molecular Biology Consortium 4/2.2 beamline at Advanced Light Source) for aid in remote data collection and help with data analysis. This research used resources of the Advanced Light Source, which is a Department of Energy Office of Science user facility under Contract DE-AC02-05CH11231. We thank Amy Whitaker (University of Kansas Medical Center) for helpful discussion and assistance with the manuscript preparation, and Scott Lovell (University of Kansas) for his advice and help with crystal optimization.

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We determined how TERT engages with telomeric DNA by co-crystallizing tcTERT with a 16-mer RNA strand hybridized to its complementary 15-mer DNA strand to form a binary complex. This substrate mimics the initial TERT:RNA complex bound to telomeric DNA (Figure 1A, state A6). In this orientation, an unpaired 5’ cytosine (rC) of the RNA strand acts as the templating base and a 3’ adenosine (dA) of the DNA strand serves as the primer terminus (Figure 1B,C). Crystals of this complex grew in a P3221 space group, diffracting to 2/5 Å resolution (Supplementary file 2, Table 2a). The resulting structure shows TERT bound as a ring around the end of the RNA:DNA complex, with its active site positioned at the terminus of the DNA strand (Figure 1B,C).

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While this has been shown by others in cells using altered nucleotide insertion into telomeres, there are no cell-based studies in the present studies to confirm or progress much of the speculation in the Discussion since all experiments in the present studies use a somewhat artificial in vitro (test tube) approach. For example, do altered ribonucleotides persist in telomeres and is there any evidence that RER removes them? Also, what is the evidence that a single misinsertion every 10kb would prevent shelterin binding or disrupt G-quadruplex stability? Even with these concerns, the studies are important to help future studies confirm and extend these finding.

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We agree that rGTP presence alone exhibited the greatest inhibition out of any of the single ribonucleotides tested. We hypothesize that the inhibition by rGTP is caused by factors in the telomeric sequence. Because the first templating base is an rC in our experimental setup, the first insertion event will be rGTP. In cases where that is successful, the next base in the sequence is also an rC, requiring the extension from a potentially unstable primer terminus, followed by yet another rGTP insertion. Therefore, telomerase cannot increase telomere length much past the initial primer terminus, potentially limiting the binding and keeping it engaged to the telomere end (with only three nucleotides base pairing). With all this in mind, we do concede that unknown effects specific to guanine could also be occurring, but we cannot test these effects without altering the telomere and TR sequences, which would alter insertion efficiencies of telomerase.

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Thank you to the reviewers for this comment. We welcome a chance to expand a bit more on our structural results, and have added more descriptions throughout that section, including how R194’s position and environment change throughout the catalytic cycle. Please see changes to the Results section.

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We are grateful to the reviewers for commenting that base-identity could also play a role in ribonucleotide tolerance. We originally thought that the number of insertions per repeat was dominating this effect, but agree that base identity and position in the template could also influence ribonucleotide tolerance by telomerase. This is particularly interesting, as rATP is present at a much higher concentration than other ribonucleotides in the cell (Traut, 1994), so it would make sense that more rATPs would be inserted, and therefore need to be tolerated. These ideas have been included in the text.

HEK293T cells were used to overexpress hTR and 3 × FLAG tagged human telomerase reverse transcriptase (hTERT) genes in pSUPER-hTR and pVan107, respectively. Cells were grown to 90% confluency in Dulbecco’s modified Eagle’s medium (Gibco) supplemented with 10% High Quality FBS (Hyclone) and 1% penicillin-streptomycin (Corning) at 37°C and 5% CO2. Cells were transfected with 10 μg of pSUPER-hTR plasmid and 2/5 μg of pVan107 hTERT plasmid diluted in 625 μl of Opti-MEM (Gibco) using 25 μl of Lipofectamine 2000 (ThermoFisher) diluted in 625 μl of Opti-MEM.

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Pre-steady-state kinetic parameters of tcTERT were obtained using established pre-steady-state kinetics protocols for DNA polymerases, also known as single turnover kinetics (Beard et al, 2021; Powers and Washington, 2021). Briefly, we preincubated 2 μM tcTERT with 200 nM annealed DNA:RNA hybrid substrate, with a 6-FAM label on the 5’ end of the DNA component. We then used a KinTek RQF-3 (a rapid quench-flow instrument) to mix equal ratios of the incoming nucleotide triphosphate of interest and 10 mM MgCl2 with the existing mix of tcTERT and its DNA:RNA hybrid substrate. Reactions were run at 37°C and quenched at various timepoints (ranging from 10 ms to 700 s) with 100 mM EDTA pH 7/5. In each case, the conditions used for each reaction were: 25 mM TRIS pH 7/5, 0/05 mg mL−1 Bovine Serum Albumin, 1 mM dithiothreitol, 10% glycerol, 200 mM KCl, 1 μM tcTERT, 100 nM annealed DNA:RNA hybrid substrate, and varying concentrations of the nucleotide triphosphate of interest. The samples were transferred to a DNA gel loading buffer, containing 100 mM EDTA, 80% deionized formamide, 0/25 mg ml−1 bromophenol blue and 0/25 mg ml−1 xylene cyanol. For the generation of data sets that had a minimum time point of 12 s or greater, a LabDoctor heating block was used in lieu of the KinTec RQF-3, and quenching was accomplished using a solution of DNA gel loading buffer. These mixes were then incubated at 95°C for 5 mins and loaded onto a 21% denaturing polyacrylamide gel. These gels were run at 700 V, 60 A, and 30 W at 30°C in order to separate the reaction product from its substrate.

We carefully chose Tribolium castaneum TERT as a model TERT with full knowledge that it lacks both the TEN domain and a large part of the IFD, compared to hTERT. We agree and wish to thank the reviewers for suggesting that we explicitly acknowledge and discuss this important difference amongst TERTs. To address this, we have created a new table further entailing the differences between several different TERTs and added text discussing these crucial differences.

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It involved partial duplex melting before the synthesis reaches the template 5' end, allowing translocation to occur. It has also been shown that the kinetics of the addition of each nt within each telomeric repeat is not the same (Chen et al, 2021). So far the structures and kinetics have only been done with one single addition of dGTP in this work, which will be different for other nucleotides of the repeat. This point needs to be carefully addressed.

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Furthermore, although structural information for category A and B structures are unknown (prenucleotide and ternary), we can compare our C category structure to the lower resolution cryo-EM structure of Tetrahymena thermophila telomerase (Jiang et al, 2021). The positions of key active site amino acids from ttTERT state C3 closely align with our state C6 (RMSD = 0/83, see Author response image 1, Figure 1—figure supplement 3 for state designations). This structural agreement between different states and homologs implies that active site contacts are similar throughout all 6 overhang lengths.

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Telomerase forms a prenucleotide bound binary complex (State A1). Then, it binds the incoming nucleotide triphosphate to form a ternary complex (State B1), chemically links it to the telomere terminus (State C1), and then shifting registry to bind the next incoming nucleotide (State A2).

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Although TERTs have highly conserved active sites, there are significant changes in the domain architecture between human and tcTERT. These include tcTERT lacking the Nterminal (TEN) domain and missing a portion of the insertion in fingers domain (IFD) (Supplementary file 1—table 1B). These domains are essential for the activity of other telomerase homologs, and have been hypothesized to be particularly important for telomerase ratcheting during translocation (Steczkiewicz et al, 2021).

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Our structural snapshots were complemented by kinetic studies, allowing us to understand how telomerase chooses right from wrong nucleotides; that is, selecting canonical dNTPs with correct base pairing compared to noncanonical rNTPs or mismatched base pairing (Figure 6A). Our experiments were carried out specifically with a single dGTP insertion using a 4 nucleotide overhang RNA template. While telomerase has been shown to exhibit moderate base and position-specific effects, our results indicate that the telomerase catalytic core generally exhibits moderate base selection fidelity, similar to that of X-family polymerases involved in DNA repair (Chen et al, 2021; McCulloch and Kunkel, 2008). Based on our kinetic values, we predict that telomerase inserts ~ 1 mismatch per each 10 kb of telomere extension. Because telomerase does not have a proofreading domain, misinsertions created by telomerase will remain as ssDNA during telomere elongation. Upon replication of the complementary strands by a DNA polymerase, the base that was a mismatch (in the context of telomerase) will become a matched base pair, and will not be a substrate for mismatch repair. Therefore, our fidelity measurement is predictive of cellular error rates in telomeric sequences. Accordingly, our predicted error rate agrees with telomeric error rates observed using telomere sequencing (Lee et al, 2021). While the downstream consequences of telomeric mismatches have not been studied in a biological context to our knowledge, they likely would disrupt G-quadruplex stability and inhibit shelterin protein binding, as both of these phenomena are dependent on DNA sequence (Figure 6B; Burge et al, 2006; de Lange, 2005).