PubMed · 7938479
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H H Rossi. 1994. Interactive DNA damage.. https://pubmed.ncbi.nlm.nih.gov/7938479/
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In this work, we shed new light on the highly debated issue of chromatin fragmentation in cryopreserved cells. Moreover, for the first time, we describe replicating cell-specific DNA damage and higher-order chromatin alterations after freezing and thawing. We identified DNA structural changes associated with the freeze-thaw process and correlated them with the viability of frozen and thawed cells. We simultaneously evaluated DNA defects and the higher-order chromatin structure of frozen and thawed cells with and without cryoprotectant treatment. We found that in replicating (S phase) cells, DNA was preferentially damaged by replication fork collapse, potentially leading to DNA double strand breaks (DSBs), which represent an important source of both genome instability and defects in epigenome maintenance. This induction of DNA defects by the freeze-thaw process was not prevented by any cryoprotectant studied. Both in replicating and non-replicating cells, freezing and thawing altered the chromatin structure in a cryoprotectant-dependent manner. Interestingly, cells with condensed chromatin, which was strongly stimulated by dimethyl sulfoxide (DMSO) prior to freezing had the highest rate of survival after thawing. Our results will facilitate the design of compounds and procedures to decrease injury to cryopreserved cells.
Three human tumour cell lines (HX142, RT112 and MGH-U1) with different radiosensitivities were tested for differences in the rate and/or extent of DNA unwinding in alkali as well as for differences in the induction of DNA double strand breaks by means of the pulsed field gel electrophoresis, after X-irradiation. Unlike that which has been found using the non-denaturing filter elution technique (NDE, McMillan et al., 1990), no differences in initial DNA damage (the extent of alkaline unwinding and the induction of double strand breaks) were found for the three cell lines. These data suggest that rather than a different number of DNA lesions per Da per Gy between these cell lines, structural differences in chromatin structure (related to radiosensitivity) might impair the detectability of lesions in some assays like the NDE. The nature of such structure differences remains unclear. However, the differences did not affect alkaline unwinding profiles, as all three cell lines showed identical rates of DNA unwinding after exposure to X-rays. Furthermore, the three cell lines did not show significant differences in the kinetics of DNA strand break rejoining nor in the amounts of damage remaining after 24 h repair. The results obtained in this study, together with other findings, suggest that the three cell lines may differ in their 'presentation' of DNA damage.
Population ecology mathematical models examine tumors not as an isolated collection of transformed individuals but as part of a dynamic society of interacting malignant and normal cells. This approach investigates the mechanisms by which a small clone of neoplastic cells is able to replace the much larger and previously stable population of normal cells, despite the numerical advantage of the latter and the inhibitory effects of the host response. The models define a sequence of different stable equilibria with critical mathematical parameters which control the outcome of different stages of the neoplasm-host competition--parameters which can be correlated with cellular physiologic properties. When neoplasm is viewed as a network of interacting tumor and normal populations, a unifying hypothesis can be developed that allows the diverse but inconsistent properties of transformed cells to be understood according to their specific contributions to tumorigenesis within this network. It predicts general sequences of genetic changes necessary for tumor survival and invasion and demonstrates that apparently disparate properties found in different tumor models can be functionally equivalent. The paper proposes novel modes of therapy requiring classification and treatment of tumors according to the strategies they employ, rather than the traditional criteria of cell type and organ of origin.