Abstract
Human tumors and cultured cells contain elevated levels of endogenous DNA damage resulting from telomere dysfunction, replication and transcription errors, reactive oxygen species, and genome instability. However, the contribution of telomere-associated versus telomere-independent endogenous DNA lesions to this damage has never been examined. In this study, we characterized the relative amounts of these two types of DNA damage in five tumor cell lines by noting whether gamma-H2AX foci, generally considered to mark DNA double-strand breaks (DSBs), were on chromosome arms or at chromosome ends. We found that while the numbers of non-telomeric DSBs were remarkably similar in these cultures, considerable variation was detected in the level of telomeric damage. The distinct heterogeneity in the numbers of gamma-H2AX foci in these tumor cell lines was found to be due to foci associated with uncapped telomeres, and the amount of total telomeric damage also appeared to inversely correlate with the telomerase activity present in these cells. These results indicate that damaged telomeres are the major factor accounting for the variability in the amount of DNA DSB damage in tumor cells. This characterization of DNA damage in tumor cells helps clarify the contribution of non-telomeric DSBs and damaged telomeres to major genomic alterations.
Highlights
Accumulation of DNA damage is a hallmark of genome instability and is associated with both aging and cancer [1,2,3]
Comparison of DNA damage in 6 intact cervical carcinoma cell lines showed great variability in γ-H2AX focal numbers, indicating that endogenous DNA damage is independent of tumor origin [10]
While the majority of the cells contained less than 10 foci per cell, there was a substantial fraction of cells that contained larger numbers of γ-H2AX foci, up to about 50 per cell, creating a long tail in the distribution and leading to large standard deviations from the average
Summary
Accumulation of DNA damage is a hallmark of genome instability and is associated with both aging and cancer [1,2,3]. Mice deficient in proteins involved in DNA damage sensing and repair exhibit severe deficiencies in these pathways leading to accelerated aging and oncogenic transformation [4]. Many progeria (premature aging) syndromes in humans are caused by mutations in genes encoding proteins involved in DNA repair and are associated with increased incidence of cancer [5, 6]. Telomeric damage is chromosome end-specific and includes two types of lesions, DNA double-strand ends which are the consequence of telomere dysfunction, and DNA DSBs at telomeres
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