Dubna, Moscow, Russian Federation
Dubna, Moscow, Russian Federation
Dubna, Moscow, Russian Federation
In this paper the mathematical description of main DNA repair pathways of single-strand break (SSB), base damage (BD), and double-strand break (DSB) in mammalian and human cells are proposed. The model shows key molecular mechanisms of DNA recovery through the single-strand DNA repair, base excision repair (BER), nonhomologous end-joining (NHEJ). To formalize the molecular mechanisms the dynamic system of differential equations describing the chemical kinetics of protein interactions according the modern concepts of molecular biology is constructed. Taking into account three repair pathways it makes possible to describe the cell's response to heavy charged particles influence. The proposed model is validated for main mechanisms of SSB repair, BER, NHEJ. In the course of the work, the time-dependent dynamics of formations and repairs of key DNA damage types (BD, SSB, DSB, cluster damages) in human cells under 56Fe ions (E = 600 Mev/u) exposure are calculated. A comparative analysis of the DNA damages and theirs repair under 12C (E = 270 MeV/u) and 56Fe (E = 600 Mev/u) ions exposure at 1 Gy was carried out.
single-strand breaks, double-strand breaks, base damages, LET, repair, modeling
1. Batmunkh M., Bayarchimeg L., Bugay A.N., Lkhagva O. Computer simulation of the DNA damage formation in neural cells under exposure to heavy charged perticles. Russian Journal of Biological Physics and Chemistry, 2019, vol. 4, no. 2, pp. 214-219. (In Russ.)
2. Zhou B.B., Elledge S.J. The DNA damage response: putting checkpoints in perspective. Nature, 2000, vol. 408, pp. 433-439.
3. Memislogu A., Samson L. Base excision repair in yeast and mammals. Mutat. Res., 2000, vol. 451, pp. 39-51.
4. Caldecott K.W. DNA Single-Strand Break Repair and Spinocerebellar Ataxia. Cell, 2003, vol. 112, pp. 7-10.
5. Kanaar R., Hoeijmakers J.H.J., van Gent D.C. Molecular mechanisms of DNA double-strand break repair. Trends Cell Biol., 1998, vol. 8, pp, 483-489.
6. Symington L.S., Gautier J. Double-strand break end resection and repair pathway choice. Annu. Rev. Genet., 2011, vol. 45, pp. 247-271.
7. Neal J.A., Meek K. Choosing the right path: does DNA-PK help make the decision? Mutat. Res. Fundam. Mol. Mech. Mut., 2011, vol. 711, pp. 73-86.
8. Robberecht C., Voet T., Esteki M.Z., Nowakowska B.A., Vermeesch J.R. Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations. Genome Res., 2013, vol. 23, pp. 411-418.
9. McVey M., Lee S.E. MMEJ repair of double-strand breaks (director’s cut): deleted sequences and alternative endings. Trends Genet., 2008, vol. 24, pp. 529-538.
10. Heyer W.D., Ehmsen K.T., Liu J. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet., 2010, vol. 44, pp. 113-139.
11. Sokhansanj B.A., Rodrigue G.R., Fitch J.P., Wilson III D.M. A quantitative model of human DNA base excision repair. I. Mechanistic insights. Nucleic Acids Res., 2002, vol. 30, no. 8, pp. 1817-1825.
12. Kesseler K.J., Kaufmann W.K., Reardon J.T., Elston T.C., Sancar A. A mathematical model for human nucleotide excision repair: damage recognition by random order assembly and kinetic proofreading. J. Theor. Biol., 2007, vol. 249, no. 2, pp. 361-375.
13. Cucinotta F.A., Pluth J.M., Anderson J.A., Harper J.V., O’Neill P. Biochemical kinetics model of DSB repair and induction of gamma-H2AX foci by non-homologous end joining. Radiat. Res., 2008, vol. 169, no. 2, pp. 214-222.
14. Taleei R., Nikjoo H. Biochemical DSB-repair model for mammalian cells in G1 and early S phases of the cell cycle. Mutation Research, 2013, vol. 756, no. 1-2, pp. 206-212.
15. Rouhani M. Modeling the interplay between DNA-PK, Artemis, and ATM in non-homologous end-joining repair in G1 phase of the cell cycle. J Biol Phys, 2019, vol. 45, no. 2, pp. 127-146.
16. Wilson III D.M., Sofinowski T.M., McNeill D.R. Repair mechanisms for oxidative damage. Front Biosci., 2003, vol. 8, pp. 963-981.
17. Lindahl T. Instability and decay of the primary structure of DNA. Nature, 1993, vol. 362, pp. 709-715.
18. Nakamura J., Walker V.E., Upton P.B., Chiang S.Y., Kow Y.W., Swenberg J.A. Highly sensitive apurinic/apyrimidinic site assay can detect spontaneous and chemically induced depurination under physical conditions. Cancer Res., 1998, vol. 58, pp. 222-225.
19. Hill J.W., Hazra T.K., Izumi T., Mitra S. Stimulation of human 8-oxoguanine-DNA glycosylase by AP-endonuclease: potential coordination of the initial steps in base excision repair. Nucleic Acids Res., 2001, vol. 29, pp. 430-438.
20. Shrivastav M., De Haro L.P., Nickoloff J.A. Regulation of DNA double-strand break repair pathway choice. Cell Res., 2008, vol. 18, no. 1, pp. 134-147.
21. Walker J.R., Corpina R.A., Goldberg J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature, 2001, vol. 412, no. 6847, pp. 607-614.
22. Yoo S., Dynan W.S. Geometry of a complex formed by double strand break repair proteins at a single DNA end: recruitment of DNA-PKcs induces inward translocation of Ku protein. Nucleic Acids Res., 1999, vol. 27, no. 24, pp. 4679-4686.
23. Uematsu N., Weterings E., Yano K., Morotomi-Yano K., Jakob B., Taucher-Scholz G., Mari P.O., van Gent D.C., Chen B.P., Chen D.J. Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks. J. Cell Biol., 2007, vol. 177, no. 2, pp. 219-229.
24. Ahnesorg P., Smith P., Jackson S.P. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell, 2006, vol. 124, no. 2, pp. 301-313.
25. Grawunder U., Wilm M., Wu X., Kulesza P., Wilson T.E., Mann M., Lieber M.R. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature, 1997, vol. 388, no. 6641, pp. 492-495.
26. Tsai C.J., Kim S.A., Chu G. Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends. Proc. Natl. Acad. Sci. U.S.A., 2007, vol. 104, no. 19, pp. 7851-7856.
27. Riballo E., Kuhne M., Rief N., Doherty A., Smith G.C., Recio M.J., Reis C., Dahm K., Fricke A., Krempler A., Parker A.R., Jackson S.P., Gennery A., Jeggo P.A., Lobrich M. A pathway of doublestrand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol. Cell, 2004, vol. 16, no. 5, pp. 715-724.
28. Goodarzi A.A., Noon A.T., Deckbar D., Ziv Y., Shiloh Y., Lobrich M., Jeggo P.A. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell, 2008, vol. 31, no. 2, pp. 167-177.
29. Darroudi F., Wiegant W., Meijers M., Friedl A.A., van der Burg M., Fomina J., van Dongen J.J., van Gent D.C., Zdzienicka M.Z. Role of Artemis in DSB repair and guarding chromosomal stability following exposure to ionizing radiation at different stages of cell cycle. Mutat. Res., 2007, vol. 615, no. 1-2, pp. 111-124.
30. Ritter S., Berger S., Groesser T., Gudowska-Novak E., Hessel P., Kehr E., Nasonova E., Kraft G. High LET Induced Chromosomal Damage in Human Fibroblasts. GSI-Report 1999-1, 1999, pp. 134-135.
