Radiation Induced Dynamic Mutations and Transgenerational Effects

Many studies have confirmed that radiation can induce genomic instability in whole body systems. Although the molecular mechanisms underlying induced genomic instability are not known at present, this interesting phenomenon could be the manifestation of a cellular fail-safe system in which fidelity of repair and replication is down-regulated to tolerate DNA damage. Two features of genomic instability namely, delayed mutation and untargeted mutation, require two mechanisms of ;damage memory\u27 and ;damage sensing, signal transduction and execution\u27 to induce mutations at a non damaged-site. In this report, the phenomenon of transgenerational genomic instability and possible mechanisms are discussed using mouse data collected in our laboratory as the main bases

Indirect mechanisms of genomic instability and the biological significance of mutations at tandem repeat loci

Radiation induction of genomic instability has two features: induction of untargeted mutation and delayed mutation. These phenomena have been studied mostly in tissue culture cells, but analyses have also been conducted in whole body systems. The study of response in whole body systems frequently applies repeat sequences as markers to detect mutations. These studies have generated conflicting findings. In addition, lack of knowledge of the mechanisms involved in repeat mutation confounds the interpretation of the biological significance of increased rates of repeat mutation. In this review, some of the existing controversies of genomic instability are discussed in relation to the mechanism of repeat mutation. Analyses of published and unpublished studies indicate a mechanistic similarity between radiation-induced genomic instability at repeat loci and dynamic mutations of triplet repeats. Because of their repetitive nature, repeat sequences frequently block progression of replication forks and are consequently resolved by slippage and/or recombination. Irradiation of cells induces S checkpoints and promotes slippage/recombination mediated repeat mutations. Thus, genomic instability at repeat loci might be viewed as a consequence of cellular attempts to restore the stability of replication in the face of the stalled replication fork; this process can occur both spontaneously as well as after exposure to radiation

Radiation carcinogenesis in mouse thymic lymphomas

Ionizing radiation is a well-known carcinogen for various human tissues and a complete carcinogen that is able to initiate and promote neoplastic progression. Studies of radiation-induced mouse thymic lymphomas, one of the classic models in radiation carcinogenesis, demonstrated that even the unirradiated thymus is capable of developing into full malignancy when transplanted into the kidney capsule or subcutaneous tissue of irradiated mice. This suggests that radiation targets tissues other than thymocytes to allow expansion of cells with tumorigenic potential in the thymus. The idea is regarded as the \u27indirect mechanism\u27 for tumor development. This paper reviews the indirect mechanism and genes affecting the development of thymic lymphomas that we have analyzed. One is the Bcl11b/Rit1 tumor suppressor gene and the other is Mtf-1 gene affecting tumor susceptibility

Continuous Propagation of Radiation Leukemia Virus on a C57BL Mouse-Embryo Fibroblast Line, with Attenuation of Leukemogenic Activity

The radiation leukemia virus (RadLV), a murine leukemia virus derived from thymic lymphomas induced by x-irradiation in strain C57BL/Ka mice, has been successfully propagated in sustained high titer in vitro in a newly established line, BL-5, of C57BL/Ka mouse-embryo fibroblasts. In addition, the production of endogenous virus, presumed to be RadLV, has been induced and sustained through multiple serial passages after treatment of BL-5 cell cultures with 5-bromodeoxyuridine. The chronically RadLV-infected subline, designated BL-5 (RadLV), sheds virus into the supernatant culture fluids that is biologically active in vitro in the XC cell plaque assay, in interference assays for focus-formation by murine sarcoma virus, and in the intracellular induction of group-specific antigens detectable by immunofluorescence, but is apparently devoid of leukemogenic activity after intrathymic inoculation into neonatal or immunosuppressed C57BL/Ka mice. Although BL-5 cells exhibited morphological alterations suggestive of transformation in vitro and gave rise to fibrosarcomatous ascites tumors after intraperitoneal inoculation with C57BL/Ka mice, the chronically infected BL-5(RadLV) cells remained normal in morphology and failed to yield fibrosarcomas in vivo