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Crystal structure of the catalytic core of human DNA polymerase kappa.

Uljon SN, Johnson RE, Edwards TA, Prakash S, Prakash L, Aggarwal AK
Structure 12 1395-404 (2004)
Cited: 74 times
EuropePMC logo PMID: 15296733

Abstract

We present the crystal structure of the catalytic core of human DNA polymerase kappa (hPolkappa), the first structure of a human Y-family polymerase. hPolkappa is implicated in the proficient extension of mispaired primer termini on undamaged DNAs, and in the extension step of lesion bypass. The structure reveals a stubby "fingers" subdomain, which despite its small size appears to be tightly restrained with respect to a putative templating base. The structure also reveals a novel "thumb" subdomain that provides a basis for the importance of the N-terminal extension unique to hPolkappa. And, most surprisingly, the structure reveals the polymerase-associated domain (PAD) juxtaposed on the dorsal side of the "palm" subdomain, as opposed to the fingers subdomain. Together, these properties suggest that the hPolkappa active site is constrained at the site of the templating base and incoming nucleotide, but the polymerase is less constrained following translocation of the lesion.

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  1. Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism. Yang W, Gao Y. Annu Rev Biochem 87 239-261 (2018)
  2. An overview of Y-Family DNA polymerases and a case study of human DNA polymerase η. Yang W. Biochemistry 53 2793-2803 (2014)
  3. Structure and function relationships in mammalian DNA polymerases. Hoitsma NM, Whitaker AM, Schaich MA, Smith MR, Fairlamb MS, Freudenthal BD. Cell Mol Life Sci 77 35-59 (2020)

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  1. Variants of mouse DNA polymerase κ reveal a mechanism of efficient and accurate translesion synthesis past a benzo[a]pyrene dG adduct. Liu Y, Yang Y, Tang TS, Zhang H, Wang Z, Friedberg E, Yang W, Guo C. Proc Natl Acad Sci U S A 111 1789-1794 (2014)
  2. Somatic Mutations in Catalytic Core of POLK Reported in Prostate Cancer Alter Translesion DNA Synthesis. Yadav S, Mukhopadhyay S, Anbalagan M, Makridakis N. Hum Mutat 36 873-880 (2015)
  3. Cryo-EM structure of human Pol κ bound to DNA and mono-ubiquitylated PCNA. Lancey C, Tehseen M, Bakshi S, Percival M, Takahashi M, Sobhy MA, Raducanu VS, Blair K, Muskett FW, Ragan TJ, Crehuet R, Hamdan SM, De Biasio A. Nat Commun 12 6095 (2021)
  4. Amino acid architecture that influences dNTP insertion efficiency in Y-family DNA polymerase V of E. coli. Seo KY, Yin J, Donthamsetti P, Chandani S, Lee CH, Loechler EL. J Mol Biol 392 270-282 (2009)
  5. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  6. The Structural Rule Distinguishing a Superfold: A Case Study of Ferredoxin Fold and the Reverse Ferredoxin Fold. Nishina T, Nakajima M, Sasai M, Chikenji G. Molecules 27 3547 (2022)


Reviews citing this publication (13)

  1. Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Prakash S, Johnson RE, Prakash L. Annu Rev Biochem 74 317-353 (2005)
  2. Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance. Waters LS, Minesinger BK, Wiltrout ME, D'Souza S, Woodruff RV, Walker GC. Microbiol Mol Biol Rev 73 134-154 (2009)
  3. Translesion DNA polymerases in eukaryotes: what makes them tick? Vaisman A, Woodgate R. Crit Rev Biochem Mol Biol 52 274-303 (2017)
  4. Y-family DNA polymerases in mammalian cells. Guo C, Kosarek-Stancel JN, Tang TS, Friedberg EC. Cell Mol Life Sci 66 2363-2381 (2009)
  5. Structural diversity of the Y-family DNA polymerases. Pata JD. Biochim Biophys Acta 1804 1124-1135 (2010)
  6. Portraits of a Y-family DNA polymerase. Yang W. FEBS Lett 579 868-872 (2005)
  7. The roles of DNA polymerase ζ and the Y family DNA polymerases in promoting or preventing genome instability. Sharma S, Helchowski CM, Canman CE. Mutat Res 743-744 97-110 (2013)
  8. Separate roles of structured and unstructured regions of Y-family DNA polymerases. Ohmori H, Hanafusa T, Ohashi E, Vaziri C. Adv Protein Chem Struct Biol 78 99-146 (2009)
  9. Adaptation to DNA damage and stimulation of genetic instability: the double-edged sword mammalian DNA polymerase kappa. Bavoux C, Hoffmann JS, Cazaux C. Biochimie 87 637-646 (2005)
  10. Recent insight into the kinetic mechanisms and conformational dynamics of Y-Family DNA polymerases. Maxwell BA, Suo Z. Biochemistry 53 2804-2814 (2014)
  11. Mammalian DNA Polymerase Kappa Activity and Specificity. Stern HR, Sefcikova J, Chaparro VE, Beuning PJ. Molecules 24 E2805 (2019)
  12. Structural and Molecular Kinetic Features of Activities of DNA Polymerases. Kuznetsova AA, Fedorova OS, Kuznetsov NA. Int J Mol Sci 23 6373 (2022)
  13. [Structural Basis of the Multifunctional Hub Protein and Identification of a Small-molecule Compound for Drug Discovery]. Hara K. Yakugaku Zasshi 139 969-973 (2019)

Articles citing this publication (52)

  1. What a difference a decade makes: insights into translesion DNA synthesis. Yang W, Woodgate R. Proc Natl Acad Sci U S A 104 15591-15598 (2007)
  2. Human DNA polymerase kappa encircles DNA: implications for mismatch extension and lesion bypass. Lone S, Townson SA, Uljon SN, Johnson RE, Brahma A, Nair DT, Prakash S, Prakash L, Aggarwal AK. Mol Cell 25 601-614 (2007)
  3. A sliding-clamp toolbelt binds high- and low-fidelity DNA polymerases simultaneously. Indiani C, McInerney P, Georgescu R, Goodman MF, O'Donnell M. Mol Cell 19 805-815 (2005)
  4. Fidelity of Dpo4: effect of metal ions, nucleotide selection and pyrophosphorolysis. Vaisman A, Ling H, Woodgate R, Yang W. EMBO J 24 2957-2967 (2005)
  5. Role for DNA polymerase kappa in the processing of N2-N2-guanine interstrand cross-links. Minko IG, Harbut MB, Kozekov ID, Kozekova A, Jakobs PM, Olson SB, Moses RE, Harris TM, Rizzo CJ, Lloyd RS. J Biol Chem 283 17075-17082 (2008)
  6. Stepwise translocation of Dpo4 polymerase during error-free bypass of an oxoG lesion. Rechkoblit O, Malinina L, Cheng Y, Kuryavyi V, Broyde S, Geacintov NE, Patel DJ. PLoS Biol 4 e11 (2006)
  7. Human DNA polymerase iota incorporates dCTP opposite template G via a G.C + Hoogsteen base pair. Nair DT, Johnson RE, Prakash L, Prakash S, Aggarwal AK. Structure 13 1569-1577 (2005)
  8. Hoogsteen base pair formation promotes synthesis opposite the 1,N6-ethenodeoxyadenosine lesion by human DNA polymerase iota. Nair DT, Johnson RE, Prakash L, Prakash S, Aggarwal AK. Nat Struct Mol Biol 13 619-625 (2006)
  9. Complex formation of yeast Rev1 and Rev7 proteins: a novel role for the polymerase-associated domain. Acharya N, Haracska L, Johnson RE, Unk I, Prakash S, Prakash L. Mol Cell Biol 25 9734-9740 (2005)
  10. Snapshots of a Y-family DNA polymerase in replication: substrate-induced conformational transitions and implications for fidelity of Dpo4. Wong JH, Fiala KA, Suo Z, Ling H. J Mol Biol 379 317-330 (2008)
  11. Structural and functional elucidation of the mechanism promoting error-prone synthesis by human DNA polymerase kappa opposite the 7,8-dihydro-8-oxo-2'-deoxyguanosine adduct. Irimia A, Eoff RL, Guengerich FP, Egli M. J Biol Chem 284 22467-22480 (2009)
  12. Structural insight into recruitment of translesion DNA polymerase Dpo4 to sliding clamp PCNA. Xing G, Kirouac K, Shin YJ, Bell SD, Ling H. Mol Microbiol 71 678-691 (2009)
  13. Structure of human DNA polymerase kappa inserting dATP opposite an 8-OxoG DNA lesion. Vasquez-Del Carpio R, Silverstein TD, Lone S, Swan MK, Choudhury JR, Johnson RE, Prakash S, Prakash L, Aggarwal AK. PLoS One 4 e5766 (2009)
  14. Evidence for a Watson-Crick hydrogen bonding requirement in DNA synthesis by human DNA polymerase kappa. Wolfle WT, Washington MT, Kool ET, Spratt TE, Helquist SA, Prakash L, Prakash S. Mol Cell Biol 25 7137-7143 (2005)
  15. Structural insights into the generation of single-base deletions by the Y family DNA polymerase dbh. Wilson RC, Pata JD. Mol Cell 29 767-779 (2008)
  16. Translesion DNA synthesis in the context of cancer research. Knobel PA, Marti TM. Cancer Cell Int 11 39 (2011)
  17. Dynamic conformational change regulates the protein-DNA recognition: an investigation on binding of a Y-family polymerase to its target DNA. Chu X, Liu F, Maxwell BA, Wang Y, Suo Z, Wang H, Han W, Wang J. PLoS Comput Biol 10 e1003804 (2014)
  18. The N-clasp of human DNA polymerase kappa promotes blockage or error-free bypass of adenine- or guanine-benzo[a]pyrenyl lesions. Jia L, Geacintov NE, Broyde S. Nucleic Acids Res 36 6571-6584 (2008)
  19. Mechanistic consequences of temperature on DNA polymerization catalyzed by a Y-family DNA polymerase. Fiala KA, Sherrer SM, Brown JA, Suo Z. Nucleic Acids Res 36 1990-2001 (2008)
  20. Structural insights into the assembly of human translesion polymerase complexes. Xie W, Yang X, Xu M, Jiang T. Protein Cell 3 864-874 (2012)
  21. Y-family polymerase conformation is a major determinant of fidelity and translesion specificity. Wilson RC, Jackson MA, Pata JD. Structure 21 20-31 (2013)
  22. Preferred WMSA catalytic mechanism of the nucleotidyl transfer reaction in human DNA polymerase κ elucidates error-free bypass of a bulky DNA lesion. Lior-Hoffmann L, Wang L, Wang S, Geacintov NE, Broyde S, Zhang Y. Nucleic Acids Res 40 9193-9205 (2012)
  23. Homology modeling of four Y-family, lesion-bypass DNA polymerases: the case that E. coli Pol IV and human Pol kappa are orthologs, and E. coli Pol V and human Pol eta are orthologs. Lee CH, Chandani S, Loechler EL. J Mol Graph Model 25 87-102 (2006)
  24. Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η. Genna V, Gaspari R, Dal Peraro M, De Vivo M. Nucleic Acids Res 44 2827-2836 (2016)
  25. Human polymerase kappa uses a template-slippage deletion mechanism, but can realign the slipped strands to favour base substitution mutations over deletions. Mukherjee P, Lahiri I, Pata JD. Nucleic Acids Res 41 5024-5035 (2013)
  26. Elucidation of kinetic mechanisms of human translesion DNA polymerase κ using tryptophan mutants. Zhao L, Pence MG, Eoff RL, Yuan S, Fercu CA, Guengerich FP. FEBS J 281 4394-4410 (2014)
  27. Biochemical analysis of active site mutations of human polymerase η. Suarez SC, Beardslee RA, Toffton SM, McCulloch SD. Mutat Res 745-746 46-54 (2013)
  28. Biochemical characterization of eight genetic variants of human DNA polymerase κ involved in error-free bypass across bulky N(2)-guanyl DNA adducts. Song I, Kim EJ, Kim IH, Park EM, Lee KE, Shin JH, Guengerich FP, Choi JY. Chem Res Toxicol 27 919-930 (2014)
  29. Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms. Ketkar A, Maddukuri L, Penthala NR, Reed MR, Zafar MK, Crooks PA, Eoff RL. ACS Chem Biol 14 1337-1351 (2019)
  30. Mutagenic nucleotide incorporation and hindered translocation by a food carcinogen C8-dG adduct in Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4): modeling and dynamics studies. Zhang L, Rechkoblit O, Wang L, Patel DJ, Shapiro R, Broyde S. Nucleic Acids Res 34 3326-3337 (2006)
  31. Role of human DNA polymerase κ in extension opposite from a cis-syn thymine dimer. Vasquez-Del Carpio R, Silverstein TD, Lone S, Johnson RE, Prakash L, Prakash S, Aggarwal AK. J Mol Biol 408 252-261 (2011)
  32. Second-Shell Basic Residues Expand the Two-Metal-Ion Architecture of DNA and RNA Processing Enzymes. Genna V, Colombo M, De Vivo M, Marcia M. Structure 26 40-50.e2 (2018)
  33. Structural mechanism of replication stalling on a bulky amino-polycyclic aromatic hydrocarbon DNA adduct by a y family DNA polymerase. Kirouac KN, Basu AK, Ling H. J Mol Biol 425 4167-4176 (2013)
  34. Comparative Error-Free and Error-Prone Translesion Synthesis of N(2)-2'-Deoxyguanosine Adducts Formed by Mitomycin C and Its Metabolite, 2,7-Diaminomitosene, in Human Cells. Bose A, Surugihalli C, Pande P, Champeil E, Basu AK. Chem Res Toxicol 29 933-939 (2016)
  35. Conformational dynamics of a Y-family DNA polymerase during substrate binding and catalysis as revealed by interdomain Förster resonance energy transfer. Maxwell BA, Xu C, Suo Z. Biochemistry 53 1768-1778 (2014)
  36. Noncognate DNA damage prevents the formation of the active conformation of the Y-family DNA polymerases DinB and DNA polymerase κ. Nevin P, Lu X, Zhang K, Engen JR, Beuning PJ. FEBS J 282 2646-2660 (2015)
  37. Molecular modeling benzo[a]pyrene N2-dG adducts in the two overlapping active sites of the Y-family DNA polymerase Dpo4. Chandani S, Loechler EL. J Mol Graph Model 25 658-670 (2007)
  38. Six Germline Genetic Variations Impair the Translesion Synthesis Activity of Human DNA Polymerase κ. Kim JK, Yeom M, Hong JK, Song I, Lee YS, Guengerich FP, Choi JY. Chem Res Toxicol 29 1741-1754 (2016)
  39. 2.0 Å resolution crystal structure of human polκ reveals a new catalytic function of N-clasp in DNA replication. Jha V, Ling H. Sci Rep 8 15125 (2018)
  40. Characterization of Nine Cancer-Associated Variants in Human DNA Polymerase κ. Antczak NM, Walker AR, Stern HR, Leddin EM, Palad C, Coulther TA, Swett RJ, Cisneros GA, Beuning PJ. Chem Res Toxicol 31 697-711 (2018)
  41. Investigating the trade-off between folding and function in a multidomain Y-family DNA polymerase. Chu X, Suo Z, Wang J. Elife 9 e60434 (2020)
  42. The PAD region in the mycobacterial DinB homologue MsPolIV exhibits positional heterogeneity. Sharma A, Subramanian V, Nair DT. Acta Crystallogr D Biol Crystallogr 68 960-967 (2012)
  43. A nucleotide binding rectification Brownian ratchet model for translocation of Y-family DNA polymerases. Xie P. Theor Biol Med Model 8 22 (2011)
  44. Binding-Induced Conformational Changes Involved in Sliding Clamp PCNA and DNA Polymerase DPO4. Chu WT, Suo Z, Wang J. iScience 23 101117 (2020)
  45. Effects of the N terminus of mouse DNA polymerase κ on the bypass of a guanine-benzo[a]pyrenyl adduct. Liu Y, Ma X, Guo C. J Biochem 159 471-479 (2016)
  46. Mutations at the Subunit Interface of Yeast Proliferating Cell Nuclear Antigen Reveal a Versatile Regulatory Domain. Halmai M, Frittmann O, Szabo Z, Daraba A, Gali VK, Balint E, Unk I. PLoS One 11 e0161307 (2016)
  47. Effects of Active Site Mutations on Specificity of Nucleobase Binding in Human DNA Polymerase η. Ucisik MN, Hammes-Schiffer S. J Phys Chem B 121 3667-3675 (2017)
  48. Investigating the Conformational Dynamics of a Y-Family DNA Polymerase during Its Folding and Binding to DNA and a Nucleotide. Chu X, Suo Z, Wang J. JACS Au 2 341-356 (2022)
  49. Biochemical Activity of 17 Cancer-Associated Variants of DNA Polymerase Kappa Predicted by Electrostatic Properties. Pathira Kankanamge LS, Mora A, Ondrechen MJ, Beuning PJ. Chem Res Toxicol 36 1789-1803 (2023)
  50. Implications of Translesion DNA Synthesis Polymerases on Genomic Stability and Human Health. Venkadakrishnan J, Lahane G, Dhar A, Xiao W, Bhat KM, Pandita TK, Bhat A. Mol Cell Biol 43 401-425 (2023)
  51. Insights into the mismatch discrimination mechanism of Y-family DNA polymerase Dpo4. Jung H, Lee S. Biochem J 478 1769-1781 (2021)
  52. Thumb-domain dynamics modulate the functional repertoire of DNA-Polymerase IV (DinB). Okeke DC, Lidman J, Matečko-Burmann I, Burmann BM. Nucleic Acids Res 51 7036-7052 (2023)


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