The Action of Caffeine on X-Irradiated HeLa Cells: III. Enhancement of X-Ray-Induced Killing during G 2 Arrest

Busse, Paul M.; Bose, S. K.; Jones, R. W.; Tolmach, L. J.

doi:10.2307/3574780

Cited by 136 publications

(44 citation statements)

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“…Expression of T alone in human diploid cells also induces increased chromosome damage and cell death (Ray et al, 1990). In addition, when mitotic delay following DNA damage is prevented by genetic mutations Hartwell, 1988, 1990;Brown et al, 1991;Weinert et al, 1994) or by chemical treatments (Busse et al, 1977(Busse et al, , 1978Lau and Pardee, 1982) that prematurely activate cyclin B/p34 cdc2 , cells su er signi®cantly more Disregulation of mitosis by SV40 T antigen T Hung-Tse Chang et al cytogenetic damage. It is also possible that aberrant mitotic events like improper spindle formation and mitotic nondisjunction (Levine et al, 1991;Fukasawa et al, 1996) may be incited by T antigen-induced disregulation of mitotic cell cycle kinases.…”

Section: Discussionmentioning

confidence: 99%

“…This delay of entry into mitosis is believed to facilitate the repair of damaged DNA prior to chromosome condensation and segregation, thereby preserving genomic integrity. When this mitotic checkpoint is abrogated by chemical agents (Busse et al, 1977(Busse et al, , 1978Lau and Pardee, 1982;Fan et al, 1995;Powell et al, 1995;Russell et al, 1995) and gene mutations (Weinert and Hartwell, 1988;Brown et al, 1991;Weinert et al, 1994;Walworth and Bernards, 1996), cells are sensitized to DNA damaging agents, often su ering dramatic increases in chromosome aberrations and cell killing.…”

Section: T Antigen Disrupts Three Mitotic Checkpoints Critical For Mamentioning

confidence: 99%

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Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Chang

Ray

et al. 1997

Oncogene

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SV40 large T antigen (T) inactivates the tumor suppressor proteins p53 and pRb, and can induce cells to enter DNA replication at inappropriate times. We show here that T also compromises three cell cycle checkpoints that regulate the entry into and exit from mitosis. Human diploid ®broblasts infected with a retrovirus expressing T displayed an attenuated radiation-induced mitotic delay, were more susceptible to chemical-induced uncoupling of mitosis from the completion of DNA replication, and were more likely to exit mitosis and rereplicate their DNA when mitotic spindle assembly was inhibited. Consistent with altered mitotic checkpoint control, cells expressing T displayed elevated protein levels and/or associated activities of the mitotic regulatory proteins cyclin A, cyclin B, Cdc25C and p34 cdc2 . These changes in mitotic control were evident within 5 ± 10 population doublings after retroviral infection, indicating a direct e ect of T expression. Cells acutely infected with the T-expressing retrovirus su ered numerical and structural chromosome aberrations, including increases in aneuploidy, dicentric chromosomes, chromatid exchanges and chromosome breaks and gaps. These ®ndings indicate that T rapidly disrupts mitotic checkpoints that help maintain genomic stability, and suggest mechanisms by which T induces chromosome aberrations and promotes the immortalization and neoplastic transformation of human cells.

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Section: Discussionmentioning

confidence: 99%

Section: T Antigen Disrupts Three Mitotic Checkpoints Critical For Mamentioning

confidence: 99%

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Chang

Ray

et al. 1997

Oncogene

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“…It also enhanced IR-induced cytotoxicity in a cycle phase-dependent manner with synchronized G2 cells displaying the greatest increment of cell killing [9,37]. Flow cytometry was used to quantify G2 checkpoint function in diploid human fibroblasts that were immortalized by expression of telomerase [38].…”

Section: Caffeine Inhibits G2 Checkpoint Functionmentioning

confidence: 99%

Caffeine and human DNA metabolism: the magic and the mystery

Kaufmann

Heffernan

Beaulieu

et al. 2003

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The ability of caffeine to reverse cell cycle checkpoint function and enhance genotoxicity after DNA damage was examined in telomerase-expressing human fibroblasts. Caffeine reversed the ATM-dependent S and G2 checkpoint responses to DNA damage induced by ionizing radiation (IR), as well as the ATR-and Chk1-dependent S checkpoint response to ultraviolet radiation (UVC). Remarkably, under conditions in which IR-induced G2 delay was reversed by caffeine, IR-induced G1 arrest was not. Incubation in caffeine did not increase the percentage of cells entering the S phase 6-8 h after irradiation; ATM-dependent phosphorylation of p53 and transactivation of p21 Cip1/Waf1 post-IR were resistant to caffeine. Caffeine alone induced a concentration-and time-dependent inhibition of DNA synthesis. It inhibited the entry of human fibroblasts into S phase by 70-80% regardless of the presence or absence of wildtype ATM or p53. Caffeine also enhanced the inhibition of cell proliferation induced by UVC in XP variant fibroblasts. This effect was reversed by expression of DNA polymerase η, indicating that translesion synthesis of UVC-induced pyrimidine dimers by DNA pol η protects human fibroblasts against UVC genotoxic effects even when other DNA repair functions are compromised by caffeine.

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“…These observations suggest that other phenomena contribute to the radiosensitizing potential of caffeine. Indeed, several studies implicate DNArepair inhibition as an important determinant of caffeine radiosensitization Busse et al, 1978;Tolmach and Busse, 1980;Beetham and Tolmach, 1982;Iliakis and Nusse, 1983a).…”

Section: Introductionmentioning

confidence: 99%

Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks

et al. 2004

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We recently reported that two Chinese hamster mutants deficient in the RAD51 paralogs XRCC2 and XRCC3 show reduced radiosensitization after treatment with caffeine, thus implicating homology-directed repair (HDR) of DNA double-strand breaks (DSBs) in the mechanism of caffeine radiosensitization. Here, we investigate directly the effect of caffeine on HDR initiated by DSBs induced by a rare cutting endonuclease (I-SceI) into one of two direct DNA repeats. The results demonstrate a strong inhibition by caffeine of HDR in wild-type cells, and a substantial reduction of this effect in HDR-deficient XRCC3 mutant cells. Inhibition of HDR and cell radiosensitization to killing shows similar dependence on caffeine concentration suggesting a cause-effect relationship between these effects. UCN-01, a kinase inhibitor that effectively abrogates checkpoint activation in irradiated cells, has only a small effect on HDR, indicating that similar to radiosensitization, inhibition of checkpoint signaling is not sufficient for HDR inhibition. Recombination events occurring during treatment with caffeine are characterized by rearrangements reminiscent to those previously reported for the XRCC3 mutant, and immunofluorescence microscopy demonstrates significantly reduced formation of IR-specific RAD51 foci after caffeine treatment. In summary, our results identify inhibition of HDR as a significant contributor to caffeine radiosensitization.

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The Action of Caffeine on X-Irradiated HeLa Cells: III. Enhancement of X-Ray-Induced Killing during G 2 Arrest

Cited by 136 publications

References 0 publications

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Caffeine and human DNA metabolism: the magic and the mystery

Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks

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