Inefficient Bypass of an Abasic Site by DNA Polymerase eta *

Lajos Haracska, M. Todd Washington, Satya Prakash, and Louise PrakashDagger

From the Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas 77555-1061

Received for publication, September 1, 2000, and in revised form, November 6, 2000



    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

DNA polymerase eta  (Poleta ) bypasses a cis-syn thymine-thymine dimer efficiently and accurately, and inactivation of Poleta in humans results in the cancer-prone syndrome, the variant form of xeroderma pigmentosum. Also, Poleta bypasses the 8-oxoguanine lesion efficiently by predominantly inserting a C opposite this lesion, and it bypasses the O6-methylguanine lesion by inserting a C or a T. To further assess the range of DNA lesions tolerated by Poleta , here we examine the bypass of an abasic site, a prototypical noninstructional lesion. Steady-state kinetic analyses show that both yeast and human Poleta are very inefficient in both inserting a nucleotide opposite an abasic site and in extending from the nucleotide inserted. Hence, Poleta bypasses this lesion extremely poorly. These results suggest that Poleta requires the presence of template bases opposite both the incoming nucleotide and the primer terminus to catalyze efficient nucleotide incorporation.



    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Abasic (apurinic/apyrimidinic; AP)1 sites represent one of the most frequently formed DNA lesions in eukaryotic cells. Base loss can occur by spontaneous hydrolysis of the N-glycosylic bond or by the action of DNA glycosylases on damaged bases. It has been estimated that a mammalian cell loses up to 10,000 purines/day from its genome (1). In eukaryotes, AP sites are efficiently repaired by excision repair processes (2-4). However, if not removed, they present a block to the replication machinery. Thus, to maintain the continuity of DNA during replication, AP sites encountered by the replication machinery have to be bypassed. In the yeast Saccharomyces cerevisiae, genes in the RAD6 epistasis group promote replication through DNA lesions (5-7). The REV1, REV3, and REV7 genes of this epistasis group are essential for damage-induced mutagenesis (8), including mutagenesis induced by AP sites (3). The Rev1 protein has a deoxycytidyltransferase activity that can incorporate a dCMP residue opposite an abasic site (9), and the Rev3 and Rev7 proteins associate to form DNA polymerase zeta  (10). In vitro, the combination of Rev1 and Polzeta promotes AP bypass (9).

The yeast RAD30 gene, which belongs to the RAD6 epistasis group, encodes a DNA polymerase, Poleta , that has the unique ability to efficiently replicate through a cis-syn thymine-thymine (T-T) dimer; it does so correctly by inserting two A residues across from the T-T dimer (11, 12). Human Poleta resembles yeast Poleta in replicating through the T-T dimer with the same efficiency and accuracy as through undamaged Ts (13). Consistent with the error-free bypass of the T-T dimer, inactivation of yeast and human Poleta causes UV hypermutability (7, 14, 15). Patients with the variant form of xeroderma pigmentosum are defective in Poleta (16, 17), and as a consequence, they suffer from a high incidence of UV-induced skin cancers.

In addition to the T-T dimer, yeast and human Poleta are able to bypass the 8-oxoguanine (8-oxoG) lesion efficiently and accurately (18). In contrast to eukaryotic polymerases alpha , delta , and epsilon , which preferentially incorporate an A opposite the 8-oxoG lesion, Poleta predominantly inserts a C opposite the 8-oxoG lesion (18). Also, yeast and human Poleta are able to bypass the O6-methylguanine (m6G) lesion, and they incorporate a C or a T residue opposite this lesion (19).

For DNA polymerases lacking the proofreading 3' right-arrow 5' exonuclease activity, the fidelity for nucleotide insertion depends upon the requirement of the polymerase active site for correct Watson-Crick base pairing geometry and upon the ability of bases to form proper hydrogen (H) bonding. Most DNA polymerases are highly sensitive to geometric distortions in DNA (20), and their fidelity is affected more severely by the disruption of optimal geometry than by H bonding between base pairs (21, 22). As a consequence, they are unable to incorporate nucleotides opposite lesions that distort the DNA helix.

Previously, we suggested that the ability of Poleta to bypass lesions, such as the T-T dimer, 8-oxoG, and m6G, results from an unusual tolerance of its active site for the distorted template geometries of these lesions. To further assess the range of template lesions tolerated by Poleta , here we examine the bypass of an abasic site, a prototypical noninstructional lesion. We find that Poleta inserts nucleotides opposite the AP site very poorly, and it also extends from the inserted nucleotide very inefficiently. These results suggest that Poleta requires the presence of template bases opposite both the incoming nucleotide and the primer terminus to catalyze efficient nucleotide insertion.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

DNA Polymerase Reactions-- Standard DNA polymerase reactions (10 µl) contained 40 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 1 mM dithiothreitol, 100 µg/ml bovine serum albumin, 10% glycerol, 20 nM 5' 32P-labeled oligonucleotide primer annealed to an oligonucleotide template, and dNTP in the concentrations indicated in the figure legends. Reactions were initiated by adding yeast or human Poleta at the concentrations indicated in the figure legends. After incubation for 5 min at 30 °C, reactions were terminated by the addition of 40 µl of loading buffer containing 20 mM EDTA, 95% formamide, 0.3% bromphenol blue, and 0.3% cyanol blue. The reaction products were resolved on 10 or 20% polyacrylamide gels containing 8 M urea and were dried before autoradiography at -70 °C with intensifying screens. A Molecular Dynamics STORM phosphorImager and ImageQuant software were used for quantitation. DNA substrates S-1 and S-2 were generated by annealing the 75-nt oligomer template (N75AP, 5'-AGCTACCATGCCTGCCTCAAGAGTTCGTAA0ATGCCTACACTGGAGTACCGGAGCATCGTCGTGACTGGGAAAAC-3'), which contained an AP site (a tetrahydrofuran moiety; Midland Co.) at the underlined at position 31 or a nondamaged G residue at this position, respectively, to the 32-nt 5' 32P-labeled oligomer primer (N4456, 5'-GTTTTCCCAGTCACGACGATGCTCCGGTACTC-3'). For steady-state kinetic analysis, DNA substrates S-3, S-4(G), S-4(A), S-4(T), and S-4(C) were generated by annealing a 52- nt oligomer template (5'-TTCGTATAATGCCTACACT0GAGTACCGGA GCATCGTCGTGACTGGGAAAAC-3'), which contained an AP residue at the underlined position 20 to the 32-nt and four different 33-nt 5' 32P-labeled oligomer primers (N4456 or oligonucleotides that contain N4456 with one additional G, A, T or C residue at its 3'-end, respectively). DNA substrates S-5(G), S-5(A), S-5(T), and S-5(C) were generated by annealing the N75AP oligomer template to four different 45-nt 5' 32P-labeled oligomer primers that contain oligomer N4309 (5'-GTTTTCCCAGTCACGACGATGCTCCGGTACTCCAGTGTAGGCAT-3') with one additional G, A, T, or C residue at its 3'-end. In nondamaged control DNA substrates the complementary bases were used instead of the AP site. The sequence of the DNA substrate containing the 18-nt template oligomer annealed to the 12-nt primer is shown in the figures.

Steady-state Kinetic Analyses-- Steady-state kinetic analysis for each deoxynucleotide incorporation opposite the AP site was done as described previously (23-25). Analyses of primer extension from this lesion were carried out in a similar manner, except that only the correct incoming deoxynucleotide was added to the reaction and the primer varied at the 3' primer end. Briefly, Poleta was incubated with increasing concentrations of a single deoxynucleotide (0-1000 µM) for 1 min under standard reaction conditions. Gel band intensities of the substrates and products were quantitated by PhosphorImager. The percentage of primer extended was plotted as a function of dNTP concentration, and the data were fit by nonlinear regression using SigmaPlot 5.0 to the Michaelis-Menten equation describing a hyperbola, v = (Vmax × [dNTP]/(Km + [dNTP]). Apparent Km and Vmax steady-state parameters were obtained from the best fit.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

An Abasic Site Is a Block to Yeast Poleta -- To determine whether yeast Poleta replicates past an abasic site in template DNA, we used a running start DNA substrate containing a single AP site in a 75-nt template DNA in which the DNA polymerase must synthesize 12 nt before encountering the lesion. DNA synthesis reactions were carried out in the presence of a 4-fold excess of DNA substrate over Poleta and from low to higher dNTP concentrations (0.5-50 µM). yPoleta replicated through the AP site very poorly, and even at 50 µM dNTP, only ~5% translesion synthesis occurred (Fig. 1A, lanes 5-8) compared with synthesis on a template containing a normal G residue (Fig. 1A, lanes 1-4). Furthermore, yPoleta exhibits two strong stall sites, one right before the lesion and the other opposite the lesion, indicating an inhibition of insertion across from the AP site as well as an inhibition of extension from the nucleotide inserted opposite the lesion. A stall site at the position just after the AP site indicates that elongation opposite the 5' residue next to the AP site is also inhibited.



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Fig. 1.   Translesion DNA synthesis activities of yeast Poleta on templates containing an AP site. A, running start DNA synthesis past an AP site by yPoleta . A portion of the DNA substrate adjacent to the primer-template junction is shown for the 75-nt template and the 32-nt, 5' 32P-labeled primer. The position of the undamaged G residue (in the S-2 substrate) (lanes 1-4) or the AP site (in the S-1 substrate) (lanes 5-8) in the template is indicated by asterisks. yPoleta (5 nM) was incubated with the DNA substrate (20 nM) in the presence of increasing concentration (0.5-50 µM) of each of four dNTPs. The amount of synthesis past the undamaged G or AP site is indicated. B, identification of nucleotides incorporated opposite the AP site by yPoleta . Standing start reactions were carried out on 18-nt templates containing either a G (lane 5) or an AP site (lanes 6-10) at position 13. The asterisks indicate the position of the G or the AP site in the template. Reactions were carried out in the presence of all four dNTPs (100 µM each, lanes 5 and 6), or in the presence of a single dNTP (100 µM, lanes 7-10), 20 nM DNA substrate, and 40 nM yPoleta . Reaction mixtures were resolved on a 20% denaturing polyacrylamide gel; electrophoretic mobilities of the 18- and 13-nt synthetic oligomers representing full-length products and primer extended by one nucleotide, respectively, and containing either a C, A, T, or G at position 13 are shown in lanes 1-4, respectively. N, all four dNTPs.

Deoxynucleotides Inserted Opposite the AP Site by Yeast Poleta -- To identify the deoxynucleotide inserted opposite the AP site, we assayed yPoleta on an 18-nt template having either a G or an AP site at position 13 from the 3' end in the template, primed with a 12-nt primer (Fig. 1B) in the presence of a single or all four nucleotides. As markers, we used the 13- and 18-nt oligomers representing a primer extended by one nucleotide and full-length products, respectively, and containing a C, A, T, or G residue at position 13, which can be distinguished by their relative electrophoretic mobility on 20% polyacrylamide gels (Fig. 1B, lanes 1-4). To facilitate bypass, we used high yPoleta as well as high dNTP concentrations, which on the undamaged G template resulted in 100% synthesis to the end of the template DNA (Fig. 1B, lane 5). Even under these forcing conditions, yPoleta carried out almost no AP bypass, and only nucleotide incorporation opposite the AP site without further extension was observed (Fig. 1B, lane 6). In the presence of all four dNTPs, yPoleta inserted primarily a G residue (95%) across from the AP site (Fig. 1B, lane 6). With only a single nucleotide present besides a G residue, yPoleta also incorporated an A, and T was inserted very weakly opposite the AP site (Fig. 1B, lanes 7-10).

Steady-state Kinetic Analyses of Nucleotide Insertion Opposite the AP Site and of Subsequent Extension by Yeast Poleta -- Next we measured the kinetics of nucleotide insertion and extension during DNA synthesis past the AP site. To determine the frequency of nucleotide incorporation by yPoleta , we measured the Km and Vmax steady-state kinetic parameters (23-25) for all four incoming dNTPs opposite a template AP site. For purposes of comparison, the kinetic parameters opposite nondamaged template residues were measured as well. yPoleta was incubated with the DNA substrate and with increasing concentrations of one of the four deoxynucleotides. The pattern of deoxynucleotide incorporation by yPoleta opposite an AP site is shown in Fig. 2A. The Km and Vmax parameters were determined and used to calculate the percentage of each nucleotide incorporated opposite the AP site (Table I). yPoleta incorporated 59% G, 31% A, 7% T, and 3% C opposite the AP site. This analysis indicates that yPoleta incorporates a G opposite the AP site with a 2-fold higher efficiency than A. Importantly, however, yPoleta inserts a G opposite the AP site about 1,000-fold less efficiently than the insertion of G opposite C (Table I). The other nucleotides were inserted even less efficiently (Table I). The substantially lower efficiency of nucleotide incorporation opposite an AP site relative to a nondamaged template residue results from a 1,000-10,000-fold increase in the Km for dNTP (Table I).



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Fig. 2.   Insertion and extension reactions catalyzed by yeast Poleta on an AP site containing DNA template. A, deoxynucleotide incorporation across from a template AP site. yPoleta (5 nM) was incubated with the S-3 primer-template DNA substrate (20 nM) and increasing concentrations (0-1000 µM) of a single deoxynucleotide (dGTP, dATP, dTTP, or dCTP) in standard reaction buffer. The quenched samples were analyzed by 10% denaturing polyacrylamide gel electrophoresis. B, extension of primers containing a G, A, T, or C residue opposite the AP site in the template by yPoleta . Primers differing only in the last nucleotide at the 3'-end were annealed separately to an AP site containing DNA template as shown on the top. Reactions were performed in the presence of increasing dATP concentrations (0-1000 µM) as described for panel A.


                              
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Table I
Kinetic parameters of insertion reactions catalyzed by yeast Poleta

For lesion bypass to occur, it is important that, after incorporating a nucleotide opposite the lesion, a polymerase extend the primer beyond the lesion. To examine the efficiency of extension past the AP site, the steady-state kinetic parameters of the addition of the next correct deoxynucleotide by yPoleta on substrates in which the 3' terminus of the primer is paired with an AP site were measured. Fig. 2B presents the pattern of extension from G, A, T, or C when paired with an AP site. From the pattern of extension from these different 3' termini, the Km and Vmax parameters were obtained and used to calculate the efficiency (Vmax/Km) of extension. The ratio of extension opposite from the AP site was: G:A:T:C = 49:37:9:5 (Table II), which indicates that yPoleta extends from a G or an A opposite the AP site about equally well. yPoleta , however, extends from G or A quite inefficiently, as the efficiency (Vmax/Km) of extension in both cases was reduced by almost 1000-fold that from the opposite nondamaged complementary bases (Table II). The lower efficiency of extension from bases opposite an AP site relative to the extension from bases opposite a nondamaged residue was also because of a 500-2000-fold increase in the Km for dNTP (Table II). Hence, yPoleta is very inefficient in inserting nucleotides across from an AP site as well as in extending from the nucleotide inserted.


                              
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Table II
Kinetic parameters of extension reactions catalyzed by yeast Poleta

Inefficient Nucleotide Insertion Opposite an AP Site and Inefficient Extension of Inserted Nucleotide by Human Poleta -- We also examined the ability of the human DNA polymerase eta  (hPoleta ) to bypass the AP site. Like yPoleta , hPoleta bypasses the AP site very inefficiently. hPoleta also exhibits two stall sites, one right before the AP site and the other opposite the lesion, indicating that there is inhibition of deoxynucleotide insertion opposite the AP site as well as inhibition of extension from this lesion (data not shown). The extremely restricted ability of hPoleta to bypass an AP site is further reflected in its steady-state Km and Vmax kinetic values. The kinetics of insertion of a single deoxynucleotide opposite an AP site and the kinetics of addition of the next correct nucleotide to various 3'-primer termini situated across from the AP site were determined as a function of deoxynucleotide concentration. hPoleta also inserts a G somewhat better than an A opposite the AP site. However, hPoleta inserts these nucleotides opposite the AP site ~103-fold less efficiently than opposite the nondamaged complementary base, because of a 600-2,500-fold increase in the Km for dNTP (Table III). The order and the ratio of deoxynucleotide insertion opposite the AP site by hPoleta were G:A:C:T ~ 13:10:1.5:1 (Table III). hPoleta also extends inefficiently from the nucleotide inserted opposite the AP site, and the order and the frequency of extension from different 3'-terminal deoxynucleotides paired with the AP site were A:G:C:T ~ 5:2:2:1 (Table IV). Thus, human Poleta inserts G slightly better than A opposite the AP site, but it is 2.5-fold more efficient at extending from an A opposite the AP site than from a G opposite this lesion. The poor extension efficiency of hPoleta is again because of a 500-1500-fold increase in the Km for dNTP (Table IV).


                              
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Table III
Kinetic parameters of insertion reactions catalyzed by human Poleta


                              
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Table IV
Kinetic parameters of extension reactions catalyzed by human Poleta



    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Poleta is unique among eukaryotic DNA polymerases in its ability to bypass a cis-syn T-T dimer and an 8-oxoG lesion efficiently and accurately. Although a cis-syn T-T dimer disrupts the DNA helix, this distortion does not affect the ability of two Ts in the dimer to base pair with As (26-28). 8-oxoG in the syn conformation mimics T and has the correct geometry to base pair with A, whereas 8-oxoG in the anti-conformation base pairs with C (29-32). The template strand, however, is significantly distorted in the vicinity of the lesion in the 8-oxoG·C base pair (29-32). Both yeast and human Poleta incorporate As opposite the two Ts of the T-T dimer with the same efficiency and accuracy as opposite undamaged Ts (12, 13). In contrast with eukaryotic replicative polymerases alpha , delta , and epsilon , which all bypass 8-oxoG by incorporating an A opposite the lesion, Poleta bypasses 8-oxoG by inserting predominantly a C opposite the lesion (18). These and other observations (19) have suggested that Poleta is refractory to geometric distortions conferred upon DNA by these lesions.

Here we examine the ability of Poleta to bypass an AP site. An abasic site is a prototypical noninstructional DNA lesion. NMR studies have indicated that DNA containing an A opposite the AP site retains all aspects of B-form DNA, and the unpaired A and the abasic residue lie inside the helix (33-35). The A is held well in the helix as if paired with T, and the melting temperature of the A· AP site is the same as that of the A·T base pair (33-35). At low temperatures, a G opposite the AP site is also predominantly intrahelical (35). However, when a pyrimidine is positioned opposite the AP site, both the pyrimidine and the abasic sugar are extrahelical, and the helix collapses (35). Many DNA polymerases insert an A opposite the AP site (36), presumably because the geometry of an A opposite an AP site closely resembles an A·T base pair.

As revealed from steady-state kinetic analyses of nucleotide insertion and extension, both yeast and human Poleta incorporate nucleotides opposite the AP site very inefficiently, and they are also highly inefficient in subsequent extension of the primer. This suggests that Poleta requires the presence of template bases opposite both the incoming nucleotide and the primer terminus to catalyze efficient nucleotide incorporation. In the absence of either of these template bases, either the enzyme or the enzyme-bound DNA substrate may adopt a conformation that is not conducive to nucleotide incorporation. Such a conformational alteration could then result in weaker dNTP binding to the enzyme-DNA complex resulting in the substantial increase in the Km for dNTP observed in both the incorporation opposite an AP site and the extension from bases opposite the AP site.

Although the results reported here provide no compelling evidence for a role of Poleta in AP bypass, they do not exclude the possibility that association with accessory factors modifies the damage bypass ability of this polymerase. In Escherichia coli, RecA stimulates the DNA synthesis efficiency of the UmuCD' complex (PolV) 15,000-fold, and the increased efficiency is reflected mainly in the Km reduction for dNTPs (37). By reducing the Km for dNTPs, accessory factors may facilitate AP bypass by promoting nucleotide incorporation opposite the lesion by Poleta .


    FOOTNOTES

* This work was supported by National Institutes of Health Grant GM19261.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Sealy Center for Molecular Science, University of Texas Medical Branch, 6.104 Medical Research Bldg., 11th and Mechanic St., Galveston, TX 77555-1061. Tel.: 409-747-8601; Fax: 409-747-8608; E-mail: lprakash@scms.utmb.edu.

Published, JBC Papers in Press, December 5, 2000, DOI 10.1074/jbc.M008021200


    ABBREVIATIONS

The abbreviations used are: AP, apurinic/apyrimidinic; T-T, thymine-thymine; 8-oxoG, 8-oxoguanine; nt, nucleotide(s); Poleta , polymerase eta ; hPoleta , human Poleta ; yPoleta , yeast Poleta .


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES


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