Eukaryotic polymerases ι and ζ act sequentially to bypass DNA lesions
Abstract
DNA lesions can often block DNA replication, so cells possess specialized low-fidelity, and often error-prone, DNA polymerases that can bypass such lesions and promote replication of damaged DNA. The Saccharomyces cerevisiae RAD30 and human hRAD30A encode Pol eta, which bypasses a cis-syn thymine-thymine dimer efficiently and accurately. Here we show that a related human gene, hRAD30B, encodes the DNA polymerase Pol iota, which misincorporates deoxynucleotides at a high rate. To bypass damage, Pol iota specifically incorporates deoxynucleotides opposite highly distorting or non-instructional DNA lesions. This action is combined with that of DNA polymerase Pol zeta, which is essential for damage-induced mutagenesis, to complete the lesion bypass. Pol zeta is very inefficient in inserting deoxynucleotides opposite DNA lesions, but readily extends from such deoxynucleotides once they have been inserted. Thus, in a new model for mutagenic bypass of DNA lesions in eukaryotes, the two DNA polymerases act sequentially: Pol iota incorporates deoxynucleotides opposite DNA lesions, and Pol zeta functions as a mispair extender.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Pol η inserts dGTP opposite template T even more efficiently than it inserts A opposite T, so its error rate for this mispair approaches 1.
“The most striking violation of Watson-Crick base pairing rules is exhibited by Pol , which inserts dGTP opposite template T even more efficiently than it inserts A opposite T (12-14), i.e. its error rate for this mispair approaches 1 (Fig. 1).”
From DNA Replication Fidelity (2004) · cites this paper as [14]
Cites
The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η
Masutani, C., Kusumoto, R., Yamada, A., Dohmae, N., Yokoi, M., Yuasa, M., Araki, M., Iwai, S., Takio, K., & Hanaoka, F. (1999) · Nature · doi:10.1038/21447 · Cited by 1,292 · see citing works
Efficient Bypass of a Thymine-Thymine Dimer by Yeast DNA Polymerase, Polη
Johnson, R. E., Prakash, S., & Prakash, L. (1999) · Science · doi:10.1126/science.283.5404.1001 · Cited by 736 · see citing works
Self-citation<i>hRAD30</i> Mutations in the Variant Form of Xeroderma Pigmentosum
Johnson, R. E., Kondratick, C. M., Prakash, S., & Prakash, L. (1999) · Science · doi:10.1126/science.285.5425.263 · Cited by 732 · see citing works
Self-citationThymine-Thymine Dimer Bypass by Yeast DNA Polymerase ζ
Nelson, J. R., Lawrence, C. W., & Hinkle, D. C. (1996) · Science · doi:10.1126/science.272.5268.1646 · Cited by 654 · see citing works
Biochemical Basis of DNA Replication Fidelity
Goodman, M. F., Creighton, S., Bloom, L. B., Petruska, J., & Kunkel, T. A. (1993) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409239309086792 · Cited by 446 · see citing works
Fidelity of Human DNA Polymerase η
Johnson, R. E., Washington, M. T., Prakash, S., & Prakash, L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.11.7447 · Cited by 399 · see citing works
Self-citationWong, I., Patel, S. S., & Johnson, K. A. (1991) · Biochemistry · doi:10.1021/bi00216a030 · Cited by 366 · see citing works
Huang, M.-M., Arnheim, N., & Goodman, M. F. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.17.4567 · Cited by 365 · see citing works
Gibbs, P., McGregor, W. G., Maher, V. M., Nisson, P. E., & Lawrence, C. W. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.12.6876 · Cited by 301 · see citing works
Base mispair extension kinetics. Comparison of DNA polymerase alpha and reverse transcriptase.
Mendelman, L. V., Petruska, J. A., & Goodman, M. F. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)39981-8 · Cited by 290 · see citing works
Kim, J., Patel, D., & Choi, B. (1995) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1995.tb05236.x · Cited by 240 · see citing works
Creighton, S., Bloom, L. B., & Goodman, M. F. (1995) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(95)62021-4 · Cited by 227 · see citing works
Novel Human and Mouse Homologs of Saccharomyces cerevisiae DNA Polymerase η
McDonald, J. P., Rapić-Otrin, V., Epstein, J. A., Broughton, B. C., Wang, X., Lehmann, A. R., Wolgemuth, D. J., & Woodgate, R. (1999) · Genomics · doi:10.1006/geno.1999.5906 · Cited by 183 · see citing works
Fidelity and Processivity of Saccharomyces cerevisiae DNA Polymerase η
Washington, M. T., Johnson, R. E., Prakash, S., & Prakash, L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.36835 · Cited by 181 · see citing works
Self-citationAccuracy of thymine-thymine dimer bypass by Saccharomyces cerevisiae DNA polymerase eta
Washington, M. T., Johnson, R. E., Prakash, S., & Prakash, L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050491997 · Cited by 173 · see citing works
Self-citationBridging the gap: A family of novel DNA polymerases that replicate faulty DNA
Johnson, R. E., Washington, M. T., Prakash, S., & Prakash, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12224 · Cited by 134 · see citing works
Self-citationKim, J.-K., & Choi, B.-S. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20331.x · Cited by 121 · see citing works
Fidelity of mammalian DNA replication and replicative DNA polymerases
Thomas, D. C., Roberts, J. D., Sabatino, R. D., Myers, T. W., Tan, C. K., Downey, K. M., So, A. G., Bambara, R. A., & Kunkel, T. A. (1991) · Biochemistry · doi:10.1021/bi00115a003 · Cited by 121 · see citing works
Determination of pyrimidine dimer unwinding angle by measurement of DNA electrophoretic mobility
Ciarrocchi, G., & Pedrini, A. M. (1982) · Journal of Molecular Biology · doi:10.1016/0022-2836(82)90445-4 · Cited by 93 · see citing works
Gibbs, P., Kilbey, B. J., Banerjee, S. K., & Lawrence, C. W. (1993) · Journal of Bacteriology · doi:10.1128/jb.175.9.2607-2612.1993 · Cited by 61 · see citing works
Gibbs, P., Borden, A., & Lawrence, C. W. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.11.1919 · Cited by 56 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kunkel, T. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.r400006200 · Cited by 754 · see citing works
Error-Prone Repair DNA Polymerases in Prokaryotes and Eukaryotes
Goodman, M. F. (2002) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.71.083101.124707 · Cited by 727 · see citing works
Hübscher, U., Maga, G., & Spadari, S. (2002) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.71.090501.150041 · Cited by 691 · see citing works
Y-family DNA polymerases and their role in tolerance of cellular DNA damage
Sale, J. E., Lehmann, A. R., & Woodgate, R. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3289 · Cited by 665 · see citing works
Lange, S. S., Takata, K.-I., & Wood, R. D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2998 · Cited by 615 · see citing works
Crystal Structure of a Y-Family DNA Polymerase in Action
Ling, H., Boudsocq, F., Woodgate, R., & Yang, W. (2001) · Cell · doi:10.1016/s0092-8674(01)00515-3 · Cited by 610 · see citing works
Lopes, M., Foiani, M., & Sogo, J. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2005.11.015 · Cited by 563 · see citing works
Specialized DNA Polymerases, Cellular Survival, and the Genesis of Mutations
Friedberg, E. C., Wagner, R., & Radman, M. (2002) · Science · doi:10.1126/science.1070236 · Cited by 443 · see citing works
Cancer in xeroderma pigmentosum and related disorders of DNA repair
Cleaver, J. E. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1652 · Cited by 427 · see citing works
DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes
Zeng, X., Winter, D. B., Kasmer, C., Kraemer, K. H., Lehmann, A. R., & Gearhart, P. J. (2001) · Nature Immunology · doi:10.1038/88740 · Cited by 420 · see citing works
Translesion DNA synthesis in eukaryotes: A one- or two-polymerase affair
Prakash, S., & Prakash, L. (2002) · Genes & Development · doi:10.1101/gad.1009802 · Cited by 344 · see citing works
Self-citationGoodman, M. F., & Woodgate, R. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a010363 · Cited by 317 · see citing works
Translesion DNA Synthesis and Mutagenesis in Eukaryotes
Sale, J. E. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012708 · Cited by 282 · see citing works
Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals
Shachar, S., Ziv, O., Avkin, S., Adar, S., Wittschieben, J., Reißner, T., Chaney, S., Friedberg, E. C., Wang, Z., Carell, T., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2008.281 · Cited by 284 · see citing works
Molecular Mechanisms of DNA Damage and Repair: Progress in Plants
Tuteja, N., Singh, M. B., Misra, M. K., Bhalla, P. L., & Tuteja, R. (2001) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/20014091074219 · Cited by 272 · see citing works
Ubiquitin-dependent DNA damage bypass is separable from genome replication
Daigaku, Y., Davies, A. A., & Ulrich, H. D. (2010) · Nature · doi:10.1038/nature09097 · Cited by 259 · see citing works
Mechanisms of UV-induced mutations and skin cancer
Pfeifer, G. P. (2020) · Genome Instability & Disease · doi:10.1007/s42764-020-00009-8 · Cited by 237 · see citing works
Structural Insights into the Origins of DNA Polymerase Fidelity
Beard, W. A., & Wilson, S. H. (2003) · Structure · doi:10.1016/s0969-2126(03)00051-0 · Cited by 157 · see citing works
A Reexamination of the Nucleotide Incorporation Fidelity of DNA Polymerases
Showalter, A. K., & Tsai, M.-D. (2002) · Biochemistry · doi:10.1021/bi026021i · Cited by 142 · see citing works
PCNA Ubiquitination Is Important, But Not Essential for Translesion DNA Synthesis in Mammalian Cells
Hendel, A., Krijger, P. H. L., Diamant, N., Goren, Z., Langerak, P., Kim, J., Reißner, T., Lee, K.-Y., Geacintov, N. E., Carell, T., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002262 · Cited by 132 · see citing works
Efficiency of Correct Nucleotide Insertion Governs DNA Polymerase Fidelity
Beard, W. A., Shock, D. D., Vande Berg, B. J., & Wilson, S. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m210036200 · Cited by 129 · see citing works
Kunkel, T. A., Pavlov, Y. I., & Bebenek, K. (2003) · DNA Repair · doi:10.1016/s1568-7864(02)00224-0 · Cited by 125 · see citing works
Lesion bypass in yeast cells: Pol η participates in a multi‐DNA polymerase process
Bresson, A., & Fuchs, R. P. P. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf363 · Cited by 112 · see citing works
Diamant, N., Hendel, A., Vered, I., Carell, T., Reißner, T., de Wind, N., Geacinov, N., & Livneh, Z. (2012) · Nucleic Acids Research · doi:10.1093/nar/gkr596 · Cited by 109 · see citing works
Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase η–deficient Mice
Lin, Q., Clark, A. B., McCulloch, S. D., Yuan, T., Bronson, R. T., Kunkel, T. A., & Kucherlapati, R. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-1862 · Cited by 95 · see citing works
DNA polymerases and human diseases
Sweasy, J. B., Lauper, J. M., & Eckert, K. A. (2006) · Radiation Research · doi:10.1667/rr0706.1 · Cited by 93 · see citing works
Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy?
Yamanaka, K., Chatterjee, N., Hemann, M. T., & Walker, G. C. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006842 · Cited by 87 · see citing works
Xeroderma pigmentosum genes: Functions inside and outside DNA repair
Sugasawa, K. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm282 · Cited by 83 · see citing works
Error-free replicative bypass of (6–4) photoproducts by DNA polymerase ζ in mouse and human cells
Yoon, J.-H., Prakash, L., & Prakash, S. (2010) · Genes & Development · doi:10.1101/gad.1872810 · Cited by 81 · see citing works
Self-citationBoudsocq, F. (2002) · DNA Repair · doi:10.1016/s1568-7864(02)00019-8 · Cited by 79 · see citing works
Molecular Regulation of <scp>UV</scp> ‐Induced <scp>DNA</scp> Repair
Shah, P., & He, Y. (2015) · Photochemistry and Photobiology · doi:10.1111/php.12406 · Cited by 75 · see citing works
Translesion DNA Polymerases and Cancer
Makridakis, N. M., & Reichardt, J. K. V. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00174 · Cited by 70 · see citing works
Sabbioneda, S., Bortolomai, I., Giannattasio, M., Plevani, P., & Muzi-Falconi, M. (2007) · DNA Repair · doi:10.1016/j.dnarep.2006.09.002 · Cited by 65 · see citing works
Xeroderma pigmentosum variant and error-prone DNA polymerases
Kannouche, P. (2003) · Biochimie · doi:10.1016/j.biochi.2003.10.009 · Cited by 60 · see citing works
Ziv, O., Zeisel, A., Mirlas-Neisberg, N., Swain, U., Nevo, R., Ben-Chetrit, N., Martelli, M. P., Rossi, R., Schiesser, S., Canman, C. E., et al. (2014) · Nature Communications · doi:10.1038/ncomms6437 · Cited by 59 · see citing works
Pagès, V., Santa Maria, S. R., Prakash, L., & Prakash, S. (2009) · Genes & Development · doi:10.1101/gad.1793409 · Cited by 55 · see citing works
Self-citationThe Base Substitution Fidelity of DNA Polymerase β-dependent Single Nucleotide Base Excision Repair
Matsuda, T., Vande Berg, B. J., Bebenek, K., Osheroff, W. P., Wilson, S. H., & Kunkel, T. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300170200 · Cited by 35 · see citing works
Non-bulky Lesions in Human DNA: The Ways of Formation, Repair, and Replication
Ignatov, А. V., Bondarenko, K. A., & Makarova, A. V. (2017) · Acta Naturae · doi:10.32607/20758251-2017-9-3-12-26 · Cited by 31 · see citing works
- Authors
- Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S., & Prakash, L.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Venue
- Nature
- Published
- 2000-08
- Volume
- 406
- Issue
- 6799
- Pages
- 1015-1019
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2470508052
- Cited by
- 632
- References
- 21
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 7 · 2023: 14 · 2022: 9 · 2021: 16 · 2020: 21 · 2019: 15 · 2018: 9 · 2017: 17 · 2016: 14 · 2015: 17 · 2014: 21 · 2013: 18 · 2012: 34
- FWCI
- 17.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- DNA polymerase iota, DNA polymerase zeta, DNA damage bypass, thymine-thymine dimers, error-prone DNA replication, misincorporation, DNA damage, Saccharomyces cerevisiae, human cells
- MeSH terms
- DNA Polymerase iota, Cloning, Molecular, Deoxyribonucleotides, DNA, DNA Damage, DNA-Directed DNA Polymerase, DNA Repair, HeLa Cells, Humans, Kinetics, Saccharomyces cerevisiae, Substrate Specificity, Base Pairing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review