Morphological transformation of 10T1/2 mouse embryo cells can be initiated by DNA double‐strand breaks alone

Borek, Carmia; Ong, Augustus; Morgan, William F.; Cleaver, James E.

doi:10.1002/mc.2940040311

Cited by 20 publications

(5 citation statements)

References 30 publications

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“…Low folate intake can also cause misincorporation of uracil during DNA synthesis [66, 67], potentially leading to DNA double-strand breaks [68], which in turn cause chromosome aberrations and neoplastic transformation [69]. Blount et al [70] demonstrated that both uracil mis-incorporation into DNA and high micronucleus frequency (a measure of chromosome breaks) in white blood cells from folate-deficient persons were markedly reduced after 8 weeks of folate supplementation.…”

Section: Discussionmentioning

confidence: 99%

Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer

Kim

Smith‐Warner

Spiegelman

et al. 2010

Cancer Causes Control

110

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Objective Studies of folate intake and colorectal cancer risk have been inconsistent. We examined the relation with colon cancer risk in a series of 13 prospective studies. Methods Study- and sex-specific relative risks (RRs) were estimated from the primary data using Cox proportional hazards models and then pooled using a random-effects model. Results Among 725,134 participants, 5,720 incident colon cancers were diagnosed during follow-up. The pooled multivariate RRs (95% confidence interval [CI]) comparing the highest vs. lowest quintile of intake were 0.92 (95% CI 0.84–1.00, p-value, test for between-studies heterogeneity = 0.85) for dietary folate and 0.85 (95% CI 0.77–0.95, p-value, test for between-studies heterogeneity = 0.42) for total folate. Results for total folate intake were similar in analyses using absolute intake cutpoints (pooled multivariate RR = 0.87, 95% CI 0.78–0.98, comparing ≥560 mcg/days vs. <240 mcg/days, p-value, test for trend = 0.009). When analyzed as a continuous variable, a 2% risk reduction (95% CI 0–3%) was estimated for every 100 μg/day increase in total folate intake. Conclusion These data support the hypothesis that higher folate intake is modestly associated with reduced risk of colon cancer.

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Section: Discussionmentioning

confidence: 99%

Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer

Kim

Smith‐Warner

Spiegelman

et al. 2010

Cancer Causes Control

110

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“…When genomic DNA strand breaks have been generated by the introduction of restriction endonucleases into cells, a strikingly increased frequency of chromosomal aberrations has been observed in cells reaching mitosis (6,7). In addition, restriction enzymeinduced strand breaks have been found to increase neoplastic transformation (5,8,68). Finally, unrepaired or irreparable DNA strand breaks may trigger cell death.…”

Section: Discussionmentioning

confidence: 99%

DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways.

Nelson¹,

Kastan²

1994

Mol. Cell. Biol.

741

344

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The tumor suppressor protein p53 serves as a critical regulator of a G1 cell cycle checkpoint and of apoptosis following exposure of cells to DNA-damaging agents. The mechanism by which DNA-damaging agents elevate p53 protein levels to trigger G1/S arrest or cell death remains to be elucidated. In fact, whether damage to the DNA template itself participates in transducing the signal leading to p53 induction has not yet been demonstrated. We exposed human cell lines containing wild-type p53 alleles to several different DNA-damaging agents and found that agents which rapidly induce DNA strand breaks, such as ionizing radiation, bleomycin, and DNA topoisomerase-targeted drugs, rapidly triggered p53 protein elevations. In addition, we determined that camptothecin-stimulated trapping of topoisomerase I-DNA complexes was not sufficient to elevate p53 protein levels; rather, replication-associated DNA strand breaks were required. Furthermore, treatment of cells with the antimetabolite N(phosphonoacetyl)-L-aspartate (PALA) did not cause rapid p53 protein increases but resulted in delayed increases in p53 protein levels temporally correlated with the appearance of DNA strand breaks. Finally, we concluded that DNA strand breaks were sufficient for initiating p53-dependent signal transduction after finding that introduction of nucleases into cells by electroporation stimulated rapid p53 protein elevations. While DNA strand breaks appeared to be capable of triggering p53 induction, DNA lesions other than strand breaks did not. Exposure of normal cells and excision repair-deficient xeroderma pigmentosum cells to low doses of UV light, under conditions in which thymine dimers appear but DNA replication-associated strand breaks were prevented, resulted in p53 induction attributable to DNA strand breaks associated with excision repair. Our data indicate that DNA strand breaks are sufficient and probably necessary for p53 induction in cells with wild-type p53 alleles exposed to DNA-damaging agents.

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“…Folate deficiency has been observed to induce double strand breaks (DSBs) both at the genomic level and within a highly conserved area (exons 5-8) of the p53 tumor suppressor gene (19,36). Because DSBs are associated with neoplastic transformation (37) and the p53 gene is the most frequently implicated gene in colorectal carcinogenesis (38). Genomic or gene specific DNA strand breaks, or both, may be a mechanism by which folate reduction increases colorectal carcinogenesis.…”

Section: Discussionmentioning

confidence: 98%

Dietary Folate Suppresses DMH-Induced Colon Carcinogenesis in a Rat Model and Affects DMH-Induced Expression of Four DNA Repair Enzymes

Sadik

Shaker

2012

Nutrition and Cancer

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This study investigated the potential role of folate in the dimethylhydrazine (DMH) colon cancer model in male Wistar rats. For induction of colon cancer, group 1 rats were injected subcutaneously with 30 mg DMH/kg body weight weekly for 30 wk. Group 2 received DMH vehicle. Group 3 rats received DMH as in Group 1 but their diet was supplemented with 8 mg folate/kg diet. Group 4 was fed diet supplemented with 8 mg folate/kg diet. Upregulation of DNA damage repair genes Apurinic/apyrimidinic endonuclease 1, X-ray repair complementing defective repair in Chinese hamster cells 5, 8-oxoguanine-DNA glycosylase, and proliferating cell nuclear antigen, associated with a reduction of folic acid level was observed in colons of DMH group. Reductions of these gene upregulations and a significant increase of colonic folic acid level occurred in the DMH group supplemented with folic acid and this group also had significant inhibition of tumor incidence, normal survival rate and histologically nearly normal colonic architecture. It can be concluded that folate supplementation exerts a potent protective effect on rat colon carcinogenesis via significant modulation of DNA repair, providing a mechanism by which it plays a role in the etiology of human cancer.

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Morphological transformation of 10T1/2 mouse embryo cells can be initiated by DNA double‐strand breaks alone

Cited by 20 publications

References 30 publications

Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer

Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer

DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways.

Dietary Folate Suppresses DMH-Induced Colon Carcinogenesis in a Rat Model and Affects DMH-Induced Expression of Four DNA Repair Enzymes

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