Restoration of T cell-specific V(D)J recombination in DNA-PKcs-/- mice by ionizing radiation: The effects on survival, development, and tumorigenesis Journal Article
| Authors: | Li, X. L.; Shen, S. R.; Wang, S.; Ouyang, H. H.; Li, G. C. |
| Article Title: | Restoration of T cell-specific V(D)J recombination in DNA-PKcs-/- mice by ionizing radiation: The effects on survival, development, and tumorigenesis |
| Abstract: | DNA-dependent protein kinase (DNA-PK) is a DNA-activated nuclear serine/threonine protein kinase. DNA-PK consists of a heterodimeric Ku subunit (composed of a 70 and 86 kD subunit) which binds DNA ends and targets the catalytic subunit DNA-PKcs to DNA strand breaks. DNA-PK plays a major role in the repair of double-strand breaks (DSB) induced in DNA after exposure to ionizing radiation. To better understand the nature of DNA repair defect associated with DNA-PKcs deficiency, we have established DNA-PKcs-/- mouse embryo fibroblast cell lines and DNA-PKcs-/- null mice, and investigated the response of these mutant cells and mice to DNA damage. DNA-PKcs-/- cells are hypersensitive to γ-irradiation, as evidenced by their low survival as assayed by colony formation efficiencies. Consistent with the radiation hypersensitive phenotype of the cell lines, DNA-PKcs-/- mice also display an extreme radiosensitivity, characterized by enhanced mortality after γ-irradiation. Treatment of newborn DNA-PKcs-/- mice with sublethal doses of ionizing radiation restores T cell receptor (TCR)β recombination and T cell maturation. However, radiation does not restore B cell development. All these mice eventually developed thymic lymphoma. These observations suggest an interrelationship between DSB repair, V(D)J recombination and lymphomagenesis, and provide an in vivo model to elucidate the critical pathways between the regulation of DNA DSB repair, V(D)J recombination, and the molecular mechanism of lymphoid neoplasia. |
| Keywords: | survival; controlled study; survival analysis; dna binding protein; genetics; mutation; dna-binding proteins; nonhuman; radiation dose; t lymphocyte; animal cell; mouse; animal; cytology; metabolism; mouse mutant; animals; mice; mice, knockout; dna damage; cell survival; cell division; dna repair; apoptosis; cell maturation; embryo; cell line; animal experiment; animal model; protein serine threonine kinase; radiation injury; mice, inbred c57bl; radiation exposure; radiation response; dose-response relationship, radiation; b lymphocyte; carcinogenesis; c57bl mouse; animalia; b-lymphocytes; tumorigenesis; mice, inbred strains; t lymphocyte receptor; gene rearrangement; genetic recombination; immunoglobulin variable region; protein-serine-threonine kinases; neoplasms, radiation-induced; newborn; lymphoma; ionizing radiation; radiosensitivity; mouse strain; animals, newborn; thymoma; thymus neoplasms; lymphocyte antigen receptor; fibroblast culture; receptors, antigen, t-cell, alpha-beta; cell mutant; enzyme deficiency; gene rearrangement, t-lymphocyte; v(d)j recombination; colony formation; dna dependent protein kinase; gamma radiation; gamma rays; null cell; dna-activated protein kinase; dna-pkcs; immunoglobulin structure; DNA dsb repair; male; female; article; immunoglobulin joining region |
| Journal Title: | Acta Biochimica Et Biophysica Sinica |
| Volume: | 34 |
| Issue: | 2 |
| ISSN: | 1672-9145 |
| Publisher: | Oxford University Press |
| Date Published: | 2002-01-01 |
| Start Page: | 149 |
| End Page: | 157 |
| Language: | English |
| PUBMED: | 12006988 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
Citation Impact
Related MSK Work