Abstract
Injections of exogenous DNA combined with a cytostatic agent cyclophosphamide (CP) cause illness and death in experimental mice. This phenomenon is referred to as delayed death. It has been found that fragments of exogenous DNA reach the bone marrow and enter the bone marrow cells (BMCs) 1–5 min after injections. Fragments of exogenous DNA are captured from culture medium by BMCs generated ex vivo. After joint incubation with BMCs of mice, the fragments of exogenous DNA are internalized into internal compartments in a nondegraded form. Up to 1800 kb of nucleic acid material can be present in each cell of BMCs generated ex vivo and treated with fragments of exogenous DNA. The fragments of exogenous DNA internalized in BMCs generated ex vivo of both intact and CP pretreated mice become circularized. In the case of intact mice, the fragments of exogenous DNA can form high-molecular weight structures in vivo. It is suggested that the exogenous fragments localized in BMC nuclei integrate into chromosome(s) of the recipient mouse genome when treated with CP and exogenous DNA.
Similar content being viewed by others
References
Abrams, R.A., McCormack, K., Bowles, C., and Deisseroth, A.B., Cyclephosphamide Treatment Expands the Circulating Hematopoietic Stem Cell Pool in Dogs, J. Clin. Invest., 1981, vol. 67, no. 5, pp. 1392–1399.
Alyamkina, E.A., Likhacheva, A.S., Nikolin, V.P., et al., The Effect of Exogenous DNA Associated with Protamine on the Growth of Experimental Mouse Tumors, Vopr. Onkol., 2009, vol. 55, no. 6, pp. 765–768.
Bhagwat, N., Olsen, A.L., Wang, A.T., et al., SPF-ERCCI Participates in the Fanconi Anemia Pathway of Cross-Link Repair, Mol. Cell. Biol., 2009, vol. 29, no. 24, pp. 6427–6437.
Derbyshire, M.K., Epstein, L.H., Young, C.S.H., et al., Nonhomologous Recombination in Human Cells, Mol. Cell Biol., 1994, vol. 14, no. 1, pp. 156–169.
Dolgova, E.V., Likhacheva, A.S., Orishchenko, K.E., et al., Interstrand Cross-Link Repair in DNA Molecule, Inform. Vestnik VOGiS, 2010, vol. 14, no. 2, pp. 332–356.
Dolgova, E.V., Nikolin, V.P., Popova, N.A., et al., Pathological Changes That Occur in Mice Treated with a Combination of Cyclophosphamide and Exogenous DNA (in press).
Dolgova, E.V., Proskurina, A.S., Nikolin, V.P., et al., Characteristics of Temporal Parameters of Manifestation of the Toxic Effect of Exogenous DNA Injection after Pretreatment with the Cytostatic Cyclophosphamide, Inform. Vestnik VOGiS, 2011, vol. 15, no. 4, pp. 485–492.
Dolgova, E.V., Rogachev, V.A., Nikolin, V.P., et al., Leukostimulatory Effect of Exogenous DNA Fragments Protected with Protamine in Cyclophosphamide-Induced Myelosuppression in Mice, Vopr. Onkol., 2009, vol. 55, no. 6, pp. 761–764.
Durant, S.T., et al., The SET Domain Protein Metnase Mediates Foreign DNA Integration and Links Integration to Nonhomologous End-Joining Repair, Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 50, pp. 18075–18080.
Filaci, G., Gerloni, M., Rizzi, M., et al., Spontaneous Transgenesis of Human B Lymphocytes, Gene Ther., 2004, no. 1, pp. 42–51.
Fleming, R.A., An Overview of Cyclophosphamide and Ifosfamide Pharmacology, Pharmacotherapy, 1997, vol. 17, pp. 146–154.
Fleming, R.A., An Overview of Cyclophosphamide and Ifosfamide Pharmacology, Pharmacotherapy, 1997, vol. 17, pp. 146–154.
Gosden, J. and Lawson, D., In situ Cyclic Amplification of Oligonucleotide Primed Synthesis (Cycling PRINS), in PCR Application Manual, Mannheim, Germany: Boehringer Mannheim Corp., 1995, pp. 115–118.
Hashzume, T. and Shimizu, N., Dissection of Mammalian Replicators by a Novel Plasmid Stability Assay, J. Cell Biochem., 2007, vol. 101, no. 3, pp. 552–565.
Helleday, T., Pathways for Mitotic Homologous Recombination in Mammalian Cells, Mutat. Res., 2003, nos. 1/2, pp. 103–115.
Lees-Miller, S.P. and Meek, K., Repair of DNA Double Strand Breaks by Non-Homologous End Joining, Biochimie, 2003, vol. 85, no. 11, pp. 1161–1173.
Likhacheva, A.S., Rogachev, V.A., Nikolin, V.P., et al., Participation of Exogenous DNA in the Molecular Processes That Occur in Somatic Cells, Inform. Vestnik VOGiS, 2008, vol. 12, no. 3, pp. 426–473.
Likhacheva, A.S., Nikolin, V.P., Popova, N.A., et al., Exogenous DNA Can Be Captured by Stem Cells and Be Involved in Their Rescue from Death after Lethal-Dose γ-Radiation, Gene Ther. Mol. Biol., 2007, vol. 11, pp. 305–314.
Lin, F.L., Sperle, K., and Sternberg, N., Recombination in Mouse I. Cells between DNA Introduced into Cells and Homologous Chromosomal Sequences, Proc. Natl. Acad. Sci. USA, 1985, vol. 82, no. 5, pp. 1391–1395.
Mazur, L. and Czyzewska, A., Immunocytochemical Analysis of Apoptotic Bone Marrow Cells after Treatment of Mice with WR-2721 and Chemotherapeutic Drugs, Folia Histochem. Cytobiol., 2001, vol. 39, no. 2, pp. 63–66.
Murata, S., Takasaki, N., Saiton, M., and Okada, N., Determination of the Phylogenetic Relationships among Pacific Salmonids by Using Short Interspersed Elements (SINEs) as Temporal Landmarks of Evolution, Proc. Natl. Acad. Sci. USA, 1993, vol. 90, pp. 6995–6999.
Niedernhofer, L.J., Odijk, H., Budzowska, M., et al., The Structure-Specific Endonuclease Erccl-Xpfis Required to Resolve DNA Interstrand Cross-Link-Induced Double-Strand Breaks, Mol. Cell. Biol., 2004, vol. 24, no. 13, pp. 5776–5787.
Pinkel, D., Straume, T., and Gray, J.W., Cytogenetic Analysis using Quantitative, High-Sensitivity, Fluorescence Hybridization, Proc. Natl. Acad. Sci. USA, 1986, vol. 83, no. 9, pp. 2934–2938.
Raynard, S., Niu, H., and Sung, P., DNA Double-Strand Break Processing: the Beginning of the End, Genes Dev., 2008, vol. 22, no. 21, pp. 2903–2907.
Roberts, D.B., Drosophila: A Practical Approach, Roberts, D.B., Ed., Oxford: IRL Press, 1986.
Saleh-Gohari, N., Bryant, H.E., Schultz, N., et al., Spontaneous Homologous Recombination Is Induced by Collapsed Replication Forks That Are Caused by Endogenous DNA Single-Strand Breaks, Mol. Cell. Biol., 2005, vol. 25, no. 16, pp. 7158–7169.
Salem, M.L., El-Naggar, S.A., and Cole, D.J., Cyclophosphamide Induces Bone Marrow to Yield Higher Numbers of Precursor Dendritic Cells in vitro Capable of Functional Antigen Presentation to T Cells in vivo, Vell. Immunol., 2010, vol. 261, no. 2, pp. 134–143.
Sambrook, J., Fritisch, E.F., and Maniatis, T., Molecular Cloning. A Laboratory Manual, 2nd ed., Cold Spring Harbor: Cold Spring Harbor Lab. Press, 1989.
De Silva, I.U., McHugh, P.J., Clingen, P.H., and Hartley, J.A., Defining the Roles of Nucleotide Excision Repair and Recombination in the Repair of DNA Interstrand Cross-Links in Mammalian Cells, Mol. Cell. Biol., 2000, vol. 20, no. 21, pp. 7980–7990.
Stanyon, R. and Galleni, R., A Rapid Fibroblast Culture Technique for High Resolution Karyotypes, Ital. J. Zool., 1991, vol. 58, no. 1, pp. 81–83.
Thomas, K.R., Folger, K.R., and Capecchi, M.R., High Frequency Targeting of Genes to Specific Sites in the Mammalian Genome, Cell, 1986, vol. 44, no. 3, pp. 419–428.
Wang, H., Rosidi, B., Perrault, R., et al., DNA Ligase III as a Candidate Component of Backup Pathways of Nonhomologous End Joining, Cancer Res., 2005, vol. 65, no. 10, pp. 4020–4030.
Znang, N., Liu, X., Li, L., and Legerski, R., Double-Strand Breaks Induce Homologous Recombinational Repair of Interstrand Cross-Links via Cooperation of MSH2, ERCC1-XPF, REV3, and the Fanconi Anemia Pathway, DNA Repair, 2007, vol. 6, no. 11, pp. 1670–1678.
Zou, L., Singe- and Double-Stranded DNA: Building a Trigger of ATR-Mediated DNA Damage Response, Genes Dev., 2007, vol. 21, no. 8, pp. 879–885.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © E.V. Dolgova, V.P. Nikolin, N.A. Popova, A.S. Proskurina, K.E. Orishenko, E.A. Alyamkina, Y.R. Efremov, E.R. Chernykh, A.A. Ostanin, E.M. Malkova, O.S. Taranov, V.A. Rogachev, S.V. Sidorov, S.S. Bogachev, M.A. Shurdov, 2012, published in Vavilovskii Zhurnal Genetiki i Selektsii, 2012, Vol. 16, No. 2, pp. 397–414.
Rights and permissions
About this article
Cite this article
Dolgova, E.V., Nikolin, V.P., Popova, N.A. et al. Internalization of exogenous DNA into internal compartments of murine bone marrow cells. Russ J Genet Appl Res 2, 440–452 (2012). https://doi.org/10.1134/S2079059712060056
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S2079059712060056