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Loop 1 modulates the fidelity of DNA polymerase lambda.

Bebenek K, Garcia-Diaz M, Zhou RZ, Povirk LF, Kunkel TA
Nucleic Acids Res 38 5419-31 (2010)
Cited: 24 times
EuropePMC logo PMID: 20435673

Abstract

Differences in the substrate specificity of mammalian family X DNA polymerases are proposed to partly depend on a loop (loop 1) upstream of the polymerase active site. To examine if this is the case in DNA polymerase λ (pol λ), here we characterize a variant of the human polymerase in which nine residues of loop 1 are replaced with four residues from the equivalent position in pol β. Crystal structures of the mutant enzyme bound to gapped DNA with and without a correct dNTP reveal that the change in loop 1 does not affect the overall structure of the protein. Consistent with these structural data, the mutant enzyme has relatively normal catalytic efficiency for correct incorporation, and it efficiently participates in non-homologous end joining of double-strand DNA breaks. However, DNA junctions recovered from end-joining reactions are more diverse than normal, and the mutant enzyme is substantially less accurate than wild-type pol λ in three different biochemical assays. Comparisons of the binary and ternary complex crystal structures of mutant and wild-type pol λ suggest that loop 1 modulates pol λ's fidelity by controlling dNTP-induced movements of the template strand and the primer-terminal 3'-OH as the enzyme transitions from an inactive to an active conformation.

Articles - 3mgh mentioned but not cited (3)

  1. Replication infidelity via a mismatch with Watson-Crick geometry. Bebenek K, Pedersen LC, Kunkel TA. Proc. Natl. Acad. Sci. U.S.A. 108 1862-1867 (2011)
  2. Loop 1 modulates the fidelity of DNA polymerase lambda. Bebenek K, Garcia-Diaz M, Zhou RZ, Povirk LF, Kunkel TA. Nucleic Acids Res. 38 5419-5431 (2010)
  3. 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)


Reviews citing this publication (4)

  1. Repair of double-strand breaks by end joining. Chiruvella KK, Liang Z, Wilson TE. Cold Spring Harb Perspect Biol 5 a012757 (2013)
  2. Structure-function studies of DNA polymerase λ. Bebenek K, Pedersen LC, Kunkel TA. Biochemistry 53 2781-2792 (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)
  4. Biological and therapeutic relevance of nonreplicative DNA polymerases to cancer. Parsons JL, Nicolay NH, Sharma RA. Antioxid. Redox Signal. 18 851-873 (2013)

Articles citing this publication (17)

  1. The catalytic cycle for ribonucleotide incorporation by human DNA Pol λ. Gosavi RA, Moon AF, Kunkel TA, Pedersen LC, Bebenek K. Nucleic Acids Res. 40 7518-7527 (2012)
  2. Processing of damaged DNA ends for double-strand break repair in mammalian cells. Povirk LF. ISRN Mol Biol 2012 (2012)
  3. Sustained active site rigidity during synthesis by human DNA polymerase μ. Moon AF, Pryor JM, Ramsden DA, Kunkel TA, Bebenek K, Pedersen LC. Nat. Struct. Mol. Biol. 21 253-260 (2014)
  4. Substrate-induced DNA polymerase β activation. Beard WA, Shock DD, Batra VK, Prasad R, Wilson SH. J. Biol. Chem. 289 31411-31422 (2014)
  5. Modeling DNA polymerase μ motions: subtle transitions before chemistry. Li Y, Schlick T. Biophys. J. 99 3463-3472 (2010)
  6. Structures of intermediates along the catalytic cycle of terminal deoxynucleotidyltransferase: dynamical aspects of the two-metal ion mechanism. Gouge J, Rosario S, Romain F, Beguin P, Delarue M. J. Mol. Biol. 425 4334-4352 (2013)
  7. Overhang polarity of chromosomal double-strand breaks impacts kinetics and fidelity of yeast non-homologous end joining. Liang Z, Sunder S, Nallasivam S, Wilson TE. Nucleic Acids Res. 44 2769-2781 (2016)
  8. Decision-making during NHEJ: a network of interactions in human Polμ implicated in substrate recognition and end-bridging. Martin MJ, Martin MJ, Blanco L. Nucleic Acids Res. 42 7923-7934 (2014)
  9. Hypothesis driven single nucleotide polymorphism search (HyDn-SNP-S). Swett RJ, Elias A, Miller JA, Dyson GE, Andrés Cisneros G. DNA Repair (Amst.) 12 733-740 (2013)
  10. Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer-Associated R438W DNA Polymerase Lambda Protein. Nemec AA, Bush KB, Towle-Weicksel JB, Taylor BF, Schulz V, Weidhaas JB, Tuck DP, Sweasy JB. Mol. Cancer Res. 14 1068-1077 (2016)
  11. Uniform Free-Energy Profiles of the P-O Bond Formation and Cleavage Reactions Catalyzed by DNA Polymerases β and λ. Klvaňa M, Bren U, Florián J. J Phys Chem B 120 13017-13030 (2016)
  12. Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants. Walker AR, Cisneros GA. Chem. Res. Toxicol. 30 1922-1935 (2017)
  13. Structures of the Leishmania infantum polymerase beta. Mejia E, Burak M, Alonso A, Larraga V, Kunkel TA, Bebenek K, Garcia-Diaz M. DNA Repair (Amst.) 18 1-9 (2014)
  14. Combining Evolutionary Conservation and Quantum Topological Analyses To Determine Quantum Mechanics Subsystems for Biomolecular Quantum Mechanics/Molecular Mechanics Simulations. Hix MA, Leddin EM, Cisneros GA. J Chem Theory Comput 17 4524-4537 (2021)
  15. Exonuclease 1 (Exo1) Participates in Mammalian Non-Homologous End Joining and Contributes to Drug Resistance in Ovarian Cancer. He D, Li T, Sheng M, Yang B. Med Sci Monit 26 e918751 (2020)
  16. Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints. Jamsen JA, Shock DD, Wilson SH. Nat Commun 13 3193 (2022)
  17. Analysis of diverse double-strand break synapsis with Polλ reveals basis for unique substrate specificity in nonhomologous end-joining. Kaminski AM, Chiruvella KK, Ramsden DA, Bebenek K, Kunkel TA, Pedersen LC. Nat Commun 13 3806 (2022)


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