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Molecular Docking and Molecular Dynamics Study on the Effect of ERCC1 Deleterious Polymorphisms in ERCC1-XPF Heterodimer

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Abstract

Excision repair cross complementation group 1 (ERCC1) is an important protein in the nucleotide excision repair (NER) pathway, which is responsible for removing DNA adducts induced by platinum based compounds. The heterodimer ERCC1-XPF is one of two endonucleases required for NER. Genetic variations or polymorphisms in ERCC1 gene alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors and enhances cisplatin chemotherapy in cancer patients, which functions by causing DNA damage. Therefore, ERCC1 variants have the potential to be used as a strong candidate biomarker in cancer treatments. In this study we identified five variants V116M, R156Q, A199T, S267P, and R322C of ERCC1 gene as highly deleterious. Further structural and functional analysis has been conducted for ERCC1 protein in the presence of three variants V116M, R156Q, and A199T. Occurrence of theses variations adversely affected the regular interaction between ERCC1 and XPF protein. Analysis of 20 ns molecular dynamics simulation trajectories reveals that the predicted deleterious variants altered the ERCC1-XPF complex stability, flexibility, and surface area. Notably, the number of hydrogen bonds in ERCC1-XPF mutant complexes decreased in the molecular dynamic simulation periods. Overall, this study explores the link between the ERCC1 deleterious variants and cisplatin chemotherapy for various cancers with the help of molecular docking and molecular dynamic approaches.

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References

  1. De Laat, W. L., Appeldoorn, E., Jaspers, N. G., & Hoeijmakers, J. H. (1998). The Journal of Biological Chemistry, 273, 7835–7842.

    Article  Google Scholar 

  2. Volker, M., Mone, M. J., Karmakar, P., van Hoffen, A., Schul, W., Vermeulen, W., et al. (2001). Molecular Cell, 8, 213–224.

    Article  CAS  Google Scholar 

  3. De Boer, J., & Hoeijmakers, J. H. (2000). Carcinogenesis, 21, 453–460.

    Article  Google Scholar 

  4. Jaspers, N. G., Raams, A., Silengo, M. C., Wijgers, N., Niedernhofer, L. J., Robinson, A. R., et al. (2007). American Journal of Human Genetics, 80, 457–466.

    Article  CAS  Google Scholar 

  5. Chen, P., Wiencke, J., Aldape, K., Kesler Diaz, A., Miiker, R., Kelsey, K., et al. (2000). Cancer Epidemiology, Biomarkers & Prevention, 9, 843–847.

    CAS  Google Scholar 

  6. Yu, J. J., Lee, K. B., Mu, C., Li, Q., Abernathy, T. V., et al. (2000). International Journal of Oncology, 16, 555–560.

    CAS  Google Scholar 

  7. Bradbury, P. A., Kulke, M. H., Heist, R. S., Zhou, W., Ma, C., Xu, W., et al. (2009). Pharmacogenetics and Genomics, 19(8), 613–625.

    Article  CAS  Google Scholar 

  8. Sunyaev, S., Hanke, J., Aydin, A., Wirkner, U., Zastrow, I., Reich, J., et al. (1999). Journal of Molecular Medicine, 77, 754–760.

    Article  CAS  Google Scholar 

  9. Cargill, M., Altshuler, D., Ireland, J., Sklar, P., Ardlie, K., Patil, N., et al. (1999). Nature Genetics, 22, 231–238.

    Article  CAS  Google Scholar 

  10. Chasman, D., & Adams, R. M. (2001). Journal of Molecular Biology, 307, 683–706.

    Article  CAS  Google Scholar 

  11. Ng, P. C., & Henikoff, S. (2001). Genome Research, 11, 863–874.

    Article  CAS  Google Scholar 

  12. Wang, Z., & Moult, J. (2001). Human Mutation, 17, 263–270.

    Article  Google Scholar 

  13. Ng, P. C., & Henikoff, S. (2006). Annual Review of Genomics and Human Genetics, 7, 61–80.

    Article  CAS  Google Scholar 

  14. Mooney, S. (2005). Briefings in Bioinformatics, 6, 44–56.

    Article  CAS  Google Scholar 

  15. Steward, R. E., MacArthur, M. W., Laskowski, R. A., & Thornton, J. M. (2003). TrendsGenetics, 19, 505–513.

    CAS  Google Scholar 

  16. Laskowski, R. A., & Thornton, J. M. (2008). Nature Reviews Genetics, 9, 141–151.

    Article  CAS  Google Scholar 

  17. Pruitt, K. D., Tatusova, T., & Maglott, D. R. (2007). Nucleic Acids Research, 35, 61–65.

    Article  Google Scholar 

  18. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., et al. (2000). Nucleic Acids Research, 28, 235–242.

    Article  CAS  Google Scholar 

  19. Amos, B., & Rolf, A. (1996). Nucleic Acids Research, 24, 21–25.

    Article  Google Scholar 

  20. Tsodikov, O. V., Enzlin, J. H., Scharer, O. D., & Ellenberger, T. (2005). Proceedings of the National Academy of Sciences of the United States of America, 102, 11236–11241.

    Article  CAS  Google Scholar 

  21. Kaplan, W., & Littlejohn, T. G. (2001). Briefings in Bioinformatics, 2, 195–197.

    Article  CAS  Google Scholar 

  22. Kumar, P., Henikoff, S., & Ng, P. C. (2009). Nature Protocols, 4, 1073–1081.

    Article  CAS  Google Scholar 

  23. Mi, H., Guo, N., Kejariwal, A., & Thomas, P. D. (2007). Nucleic Acids Research, 35, 247–252.

    Article  Google Scholar 

  24. Capriotti, E., Fariselli, P., Rossi, I., & Casadio, R. (2008). BMC Bioinformatics, 9(Suppl 2):S6

    Google Scholar 

  25. Ramensky, V., Bork, P., & Sunyaev, S. (2002). Nucleic Acids Research, 30, 3894–3900.

    Article  CAS  Google Scholar 

  26. Ng, P. C., & Henikoff, S. (2003). Nucleic Acids Research, 13, 3812–3814.

    Article  Google Scholar 

  27. Dominguez, C., Boelens, R., & Bonvin, A. M. (2003). Journal of the American Chemical Society, 125, 1731–1737.

    Article  CAS  Google Scholar 

  28. de Vries, S. J., van Dijk, M., & Bonvin, A. M. J. J. (2010). Nature Protocols, 5, 883–897.

    Article  Google Scholar 

  29. Nilges, M. (1995). Journal of Molecular Biology, 245, 645–660.

    Article  CAS  Google Scholar 

  30. Nilges, M., Macias, M. J., O’Donoghue, S. I., & Oschkinat, H. (1997). Journal of Molecular Biology, 269, 408–422.

    Article  CAS  Google Scholar 

  31. Brunger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse-Kunstleve, R. W., et al. (1998). Acta Crystallographica. Section D, Biological Crystallography, 54, 905–921.

    Article  CAS  Google Scholar 

  32. Hess, B., Kutzner, C., van der Spoel, D., & Lindahl, E. (2008). Journal of Chemical Theory and Computation, 4, 435–447.

    Article  CAS  Google Scholar 

  33. Kutzner, C., van der Spoel, D., Fechner, M., Lindahl, E., Schmittn, U. W., de Groot, B. L., et al. (2007). Journal of Compound Chemistry, 28, 2075–2084.

    Article  CAS  Google Scholar 

  34. Van Gunsteren, W.F., Billeter, S.R., Eising, A.A., Hunenberger, P.H., & Kruger, P. (1996). Zurich, Groningen

  35. Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., & Klein, M. L. (1983). The Journal of Chemical Physics, 79, 926.

    Article  CAS  Google Scholar 

  36. Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A., & Haak, J. R. (1984). The Journal of Chemical Physics, 81, 3684–3690.

    Article  CAS  Google Scholar 

  37. Essmann, U., Perera, L., Berkowitz, M. L., Darden, T., Lee, H., & Pedersen, L. G. (1995). The Journal of Chemical Physics, 103, 8577–8593.

    Article  CAS  Google Scholar 

  38. Case, D.A., Pearlman, D.A., Caldwell, J.W., Wang, J., Ross, W.S., Simmerling, T.A., et al. (2002). San Francisco, CA, University of California

  39. Baker, E. N., & Hubbard, R. E. (1984). Progress in Biophysics and Molecular Biology, 44, 97–179.

    Article  CAS  Google Scholar 

  40. Halperin, I., Ma, B., Wolfson, H., & Nussinov, R. (2002). Proteins: Structure, Function, and Genetics, 47, 409–443.

    Article  CAS  Google Scholar 

  41. Janin, J., Henrick, K., Moult, J., Eyck, L. T., Sternberg, M. J., Vajda, S., et al. (2003). Proteins: Structure, Function, and Genetics, 52, 2–9.

    Article  CAS  Google Scholar 

  42. Dominguez, C., Boelens, R., & Bonvin, A. M. (2003). Journal of the American Chemical Society, 125, 1731–1737.

    Article  CAS  Google Scholar 

  43. Teng, S., Madej, T., Panchenko, A., & Alexov, E. (2009). Biophysical Journal, 96(6), 2178–2188.

    Article  CAS  Google Scholar 

  44. Zhang, Z., Norris, J., Schwartz, C., & Alexov, E. (2011). PLoS One, 6(5), e2037.

    Google Scholar 

  45. Garcia, A. E. (1992). Physical Review Letters, 68, 2696–2699.

    Article  CAS  Google Scholar 

  46. Cui, Q., & Bahar, I. (2006). Chapman & Hall/CRC. FL: Boca Raton.

    Google Scholar 

  47. Pimentel, G.C., & McClellan, A.L. (1960). Freeman: San Francisco

  48. Desiraju, G., & Steiner, T. (1999). Oxford University Press: Oxford

  49. Schuster, P., Zundel, G., & Sandorfy, C. (1976). Elsevier Science Publishing. Amsterdam: North-Holland.

    Google Scholar 

  50. Gerlt, J. A., Kreevoy, M. M., Cleland, W. W., & Frey, P. A. (1997). Chemistry and Biology, 4, 259–267.

    Article  CAS  Google Scholar 

  51. Becker, O., Mackerell, A., Roux, B., Watanabe, M., & Eds. (2001). Computational Biochemistry & Biophysics, Marcel Dekker, New York

  52. Eisenberg, D., & McClachlan, A. (1986). Nature, 319, 199–203.

    Article  CAS  Google Scholar 

  53. Wesson, L., & Eisenberg, D. (1992). Protection Science, 1(2), 227–235.

    Article  CAS  Google Scholar 

  54. Fraternali, F., & van Gunsteren, W. (1996). Journal of Molecular Biology, 256, 939–948.

    Article  CAS  Google Scholar 

  55. Ferrara, P., Apostolakis, J., & Caflisch, A. (2002). Proteins, 46, 24–33.

    Article  CAS  Google Scholar 

  56. Koehl, P., & Delarue, M. (1994). Proteins, 20, 264–278.

    Article  CAS  Google Scholar 

  57. Bradbury, P. A., Kulke, M. H., Heist, R. S., Zhou, W., Ma, C., Xu, W., et al. (2009). Pharmacogenet Genomics, 19(8), 613–25.

    Article  CAS  Google Scholar 

  58. Bradbury, P. A., Kulke, M. H., Heist, R. S., Zhou, W., Ma, C., Xu, W., et al. (2009). Pharmacogenetics and Genomics, 19(8), 613–625.

    Article  CAS  Google Scholar 

  59. Giovannetti, E., Pacetti, P., Reni, M., Leon, L. G., Mambrini, A., Vasile, E., et al. (2011). Pharmacogenomics, 12, 1641–1652.

    Article  CAS  Google Scholar 

  60. Wang, Z., & Moult, J. (2001). Human Mutation, 17, 263–270.

    Article  Google Scholar 

  61. George Priya Doss, C., Sudandiradoss, C., Rajasekaran, R., Purohit, R., Ramanathan, K., & Sethumadhavan, R. (2008). Journal of Biomedical Informatics, 41, 607–612.

    Article  CAS  Google Scholar 

  62. Nagasundaram, N., & Priya Doss, C. G. (2011). Journal Carcinogenesis, 10, 26.

    Article  CAS  Google Scholar 

  63. Doss, C. G., & Nagasundaram, N. (2012). PLoS One, 7(2), e31677.

    Article  Google Scholar 

  64. Mohamed, A. J., Yu, L., Backesjo, C. M., Vargas, L., & Faryal, R. (2009). Immunological Reviews, 228, 58–73.

    Article  CAS  Google Scholar 

  65. Muller, C. W., Schlauderer, G. J., Reinstein, J., & Schulz, G. E. (1996). Structure, 4, 147–156.

    Article  CAS  Google Scholar 

  66. Vihinen, M. (1987). Protein Engineering, 1, 477–480.

    Article  CAS  Google Scholar 

  67. Bikadi, Z., Demko, L., & Hazai, E. (2007). Archives of Biochemistry and Biophysics, 461, 225–234.

    Article  CAS  Google Scholar 

  68. Ahmad, S., Gromiha, M. M., & Sarai, A. (2004). Bioinformatics, 20, 477–486.

    Article  CAS  Google Scholar 

  69. International HapMap Consortium. (2005). Nature, 27,437(7063).

  70. Collins, F. S., Guyer, M. S., & Charkravarti, A. (1997). Science, 278, 1580–1581.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors take this opportunity to thank the management of Vellore Institute of Technology University for providing the facilities and encouragement to carry out this work.

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  1. Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India

    George Priya Doss C & Nagasundaram N

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  1. George Priya Doss C
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Correspondence to George Priya Doss C.

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C, G.P.D., N, N. Molecular Docking and Molecular Dynamics Study on the Effect of ERCC1 Deleterious Polymorphisms in ERCC1-XPF Heterodimer. Appl Biochem Biotechnol 172, 1265–1281 (2014). https://doi.org/10.1007/s12010-013-0592-5

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