Telomere-dependent and telomere-independent origins of endogenous DNA damage in tumor cells

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 γ-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 γ-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.

Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma

“…Some tumor cells show elevated baseline levels of DNA damage 35 as noted in MT-2 cells and to a lower extent in Jurkat and Molt-4 cells (Figure 3D), which may be due to several factors such as chromatin instability 36 and damaged telomeres. 37 Tax has been shown to increase genetic instability by inducing DNA double strand breaks as evidenced by increased g-H2AX levels 38 ; however, other factors may be also implicated as shown by the variability in the expression of endogenous g-H2AX levels in HuT-102 and MT-2 cells.…”

A dual role for A-type lamins in DNA double-strand break repair

“…DNA DSBs repair, which occurs mainly by NHEJ and HR, is critical for maintaining genomic stability. 17,19,[53][54][55][56][57] Here, we demonstrate that the structural nuclear proteins A-type lamins preserve the integrity of the genome in part by maintaining the ability of cells to repair DNA DSBs by NHEJ and HR. We provide evidence that the mechanism which allows A-type lamins to promote long-range (dysfunctional telomeres) and short-range (IR-induced DNA DSBs) classical-NHEJ is the stabilization of 53BP1.…”

microRNA-34a promotes DNA damage and mitotic catastrophe

“…25 Such "spontaneous" foci represent endogenous DNA lesions resulting from replicative and oxidative stresses, transcription errors, dysfunctional telomeres, and genomic instability of malignant cells. 10,26 In addition, the long-lasting 53BP1 foci, which are suggested to be the sites of incomplete DNA DSB repair, are observed for as long as 14 weeks after the exogenous genotoxic stress. 27 53BP1 is detected in PML nuclear bodies, which are implicated in DNA damage repair, 10,[27][28][29] and in socalled OPT (Oct-1, PTF, transcription) domains, which shield resulting from the replication stress DNA lesions against their degradation to DSB.…”