Mutagenic Replication of N-Deoxyguanosine Benzo[a]pyrene Adducts by Escherichia Coli DNA Polymerase I and Sulfolobus Solfataricus DNA Polymerase IV

Overview

Journal Chem Res Toxicol

Publisher American Chemical Society

Specialty Toxicology

Date 2017 Apr 14

PMID 28402640

Citations 2

Authors

A S Prakasha Gowda

Jacek Krzeminski

Shantu Amin

Zucai Suo

Thomas E Spratt

Affiliations

Soon will be listed here.

Abstract

Benzo[a]pyrene, a potent human carcinogen, is metabolized in vivo to a diol epoxide that reacts with the N-position of guanine to produce N-BP-dG adducts. These adducts are mutagenic causing G to T transversions. These adducts block replicative polymerases but can be bypassed by the Y-family translesion synthesis polymerases. The mechanisms by which mutagenic bypass occurs is not well-known. We have evaluated base pairing structures using atomic substitution of the dNTP with two stereoisomers, 2'-deoxy-N-[(7R,8S,9R,10S)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine and 2'-deoxy-N-[(7S,8R,9S,10R)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine. We have examined the kinetics of incorporation of 1-deaza-dATP, 7-deaza-dATP, 2'-deoxyinosine triphosphate, and 7-deaza-dGTP, analogues of dATP and dGTP in which single atoms are changed. Changes in rate will occur if that atom provided a critical interaction in the transition state of the reaction. We examined two polymerases, Escherichia coli DNA polymerase I (Kf) and Sulfolobus solfataricus DNA polymerase IV (Dpo4), as models of a high fidelity and TLS polymerase, respectively. We found that with Kf, substitution of the nitrogens on the Watson-Crick face of the dNTPs resulted in decreased rate of reactions. This result is consistent with a Hoogsteen base pair in which the template N-BP-dG flipped from the anti to syn conformation. With Dpo4, while the substitution did not affect the rate of reaction, the amplitude of the reaction decreased with all substitutions. This result suggests that Dpo4 bypasses N-BP-dG via Hoogsteen base pairs but that the flipped nucleotide can be either the dNTP or the template.

Citing Articles

A hand-off of DNA between archaeal polymerases allows high-fidelity replication to resume at a discrete intermediate three bases past 8-oxoguanine.

Cranford M, Kaszubowski J, Trakselis M Nucleic Acids Res. 2020; 48(19):10986-10997.

PMID: 32997110 PMC: 7641752. DOI: 10.1093/nar/gkaa803.

Active Site Interactions Impact Phosphoryl Transfer during Replication of Damaged and Undamaged DNA by Escherichia coli DNA Polymerase I.

Gowda A, Spratt T Chem Res Toxicol. 2017; 30(11):2033-2043.

PMID: 29053918 PMC: 5696056. DOI: 10.1021/acs.chemrestox.7b00257.

References

Sholder G, Creech A, Loechler E . How Y-Family DNA polymerase IV is more accurate than Dpo4 at dCTP insertion opposite an N2-dG adduct of benzo[a]pyrene. DNA Repair (Amst). 2015; 35:144-53. DOI: 10.1016/j.dnarep.2015.09.020. View

Shibutani S, MARGULIS L, Geacintov N, Grollman A . Translesional synthesis on a DNA template containing a single stereoisomer of dG-(+)- or dG-(-)-anti-BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene). Biochemistry. 1993; 32(29):7531-41. DOI: 10.1021/bi00080a027. View

Denissenko M, Pao A, Tang M, Pfeifer G . Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996; 274(5286):430-2. DOI: 10.1126/science.274.5286.430. View

HAKURA A, Tsutsui Y, Sonoda J, Tsukidate K, Mikami T, Sagami F . Comparison of the mutational spectra of the lacZ transgene in four organs of the MutaMouse treated with benzo[a]pyrene: target organ specificity. Mutat Res. 2001; 447(2):239-47. DOI: 10.1016/s0027-5107(99)00213-4. View

Sale J, Lehmann A, Woodgate R . Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat Rev Mol Cell Biol. 2012; 13(3):141-52. PMC: 3630503. DOI: 10.1038/nrm3289. View

Lehmann A, Niimi A, Ogi T, Brown S, Sabbioneda S, Wing J . Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair (Amst). 2007; 6(7):891-9. DOI: 10.1016/j.dnarep.2007.02.003. View

Decarlo L, Gowda A, Suo Z, Spratt T . Formation of purine-purine mispairs by Sulfolobus solfataricus DNA polymerase IV. Biochemistry. 2008; 47(31):8157-64. PMC: 2570044. DOI: 10.1021/bi800820m. View

Chandani S, Loechler E . Y-Family DNA polymerases may use two different dNTP shapes for insertion: a hypothesis and its implications. J Mol Graph Model. 2009; 27(7):759-69. PMC: 2780423. DOI: 10.1016/j.jmgm.2008.11.003. View

Gowda A, Spratt T . DNA Polymerases η and ζ Combine to Bypass O(2)-[4-(3-Pyridyl)-4-oxobutyl]thymine, a DNA Adduct Formed from Tobacco Carcinogens. Chem Res Toxicol. 2016; 29(3):303-16. PMC: 5081176. DOI: 10.1021/acs.chemrestox.5b00468. View

10.

Chandani S, Loechler E . Molecular modeling benzo[a]pyrene N2-dG adducts in the two overlapping active sites of the Y-family DNA polymerase Dpo4. J Mol Graph Model. 2006; 25(5):658-70. DOI: 10.1016/j.jmgm.2006.05.003. View

11.

Lone S, Townson S, Uljon S, Johnson R, Brahma A, Nair D . Human DNA polymerase kappa encircles DNA: implications for mismatch extension and lesion bypass. Mol Cell. 2007; 25(4):601-14. DOI: 10.1016/j.molcel.2007.01.018. View

12.

Klarer A, Stallons L, Burke T, Skaggs R, McGregor W . DNA polymerase eta participates in the mutagenic bypass of adducts induced by benzo[a]pyrene diol epoxide in mammalian cells. PLoS One. 2012; 7(6):e39596. PMC: 3380003. DOI: 10.1371/journal.pone.0039596. View

13.

Perlow-Poehnelt R, Likhterov I, Scicchitano D, Geacintov N, Broyde S . The spacious active site of a Y-family DNA polymerase facilitates promiscuous nucleotide incorporation opposite a bulky carcinogen-DNA adduct: elucidating the structure-function relationship through experimental and computational approaches. J Biol Chem. 2004; 279(35):36951-61. DOI: 10.1074/jbc.M404332200. View

14.

Avkin S, Goldsmith M, Velasco-Miguel S, Geacintov N, Friedberg E, Livneh Z . Quantitative analysis of translesion DNA synthesis across a benzo[a]pyrene-guanine adduct in mammalian cells: the role of DNA polymerase kappa. J Biol Chem. 2004; 279(51):53298-305. DOI: 10.1074/jbc.M409155200. View

15.

Rechkoblit O, Zhang Y, Guo D, Wang Z, Amin S, Krzeminsky J . trans-Lesion synthesis past bulky benzo[a]pyrene diol epoxide N2-dG and N6-dA lesions catalyzed by DNA bypass polymerases. J Biol Chem. 2002; 277(34):30488-94. DOI: 10.1074/jbc.M201167200. View

16.

Cheng S, Hilton B, Roman J, Dipple A . DNA adducts from carcinogenic and noncarcinogenic enantiomers of benzo[a]pyrene dihydrodiol epoxide. Chem Res Toxicol. 1989; 2(5):334-40. DOI: 10.1021/tx00011a011. View

17.

Hsu G, Huang X, Luneva N, Geacintov N, Beese L . Structure of a high fidelity DNA polymerase bound to a benzo[a]pyrene adduct that blocks replication. J Biol Chem. 2004; 280(5):3764-70. DOI: 10.1074/jbc.M411276200. View

18.

Nair D, Johnson R, Prakash L, Prakash S, Aggarwal A . Hoogsteen base pair formation promotes synthesis opposite the 1,N6-ethenodeoxyadenosine lesion by human DNA polymerase iota. Nat Struct Mol Biol. 2006; 13(7):619-25. DOI: 10.1038/nsmb1118. View

19.

Buening M, Wislocki P, Levin W, Yagi H, Thakker D, Akagi H . Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. Proc Natl Acad Sci U S A. 1978; 75(11):5358-61. PMC: 392962. DOI: 10.1073/pnas.75.11.5358. View

20.

Hess M, Gunz D, Luneva N, Geacintov N, Naegeli H . Base pair conformation-dependent excision of benzo[a]pyrene diol epoxide-guanine adducts by human nucleotide excision repair enzymes. Mol Cell Biol. 1997; 17(12):7069-76. PMC: 232563. DOI: 10.1128/MCB.17.12.7069. View