On the Role of DNA Double-Strand Breaks in Toxicity and Carcinogenesis

Vamvakas, Spiros; Vock, Esther; Lutz, Werner

doi:10.3109/10408449709021617

Cited by 104 publications

(58 citation statements)

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“…We also demonstrated that deregulated Pol b results in modi®cations at the chromosomal level, the ampli®cation of the level of DNA breaks and aberrations induced by radiation, which have been speculated to play a role in the process of radiation carcinogenesis (Vamvakas et al, 1997). This suggests that high level of Pol b, which magnify these chromosomal modi®cations, may therefore predispose the minority of the cell population which survives the radiotherapy for high tumour incidence when exposed to radiations.…”

Section: Discussionmentioning

confidence: 72%

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

et al. 2002

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is an error-prone enzyme which has been found to be overexpressed in several human tumors. By using a couple of recombinant CHO cells di ering only from the exogenous expression of Pol b b, we showed here that cells overexpressing Pol b b are much more sensitive to IR treatments by increasing apoptosis. We also found that the surviving cells displayed an hypermutator phenotype which could be explained by di erent pathways involving Pol b b, such as (i) an increased capacity to incorporate into DNA the mutagenic dGTP analog, 8-oxo-dGTP, one of the most abundant purine-derived nucleotides exposed to g girradiation, (ii) the induction of IR-induced DNA breaks and (iii) accumulation of chromosome aberrations induced by radiation. Alteration of Pol b b expression in irradiated cells thus appears to strengthen both cell death and genetic changes associated with a malignant phenotype. These data provide new insights into the cellular response to radiations and the associated carcinogenic consequences.

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Section: Discussionmentioning

confidence: 72%

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

et al. 2002

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“…RONS-induced DNA lesions such as base damage, single-strand breaks, and double-strand breaks (DSBs) can be cytotoxic and thus damaging to host tissue function (9,10). DSBs are one of the most toxic forms of DNA damage (11,12). In response to DSBs, the ataxia telangiectasia mutated (ATM) kinase pathway is activated, leading to Ser-139 phosphorylation of histone H2AX, forming γH2AX.…”

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confidence: 99%

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Rai

Parrish

Tay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

129

102

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Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H 2 O 2 , plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H 2 O 2 , greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H 2 O 2 production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniaeinduced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.DNA damage | Streptococcus pneumoniae | hydrogen peroxide | γH2AX | Ku80

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“…Elevated top1 protein levels increase the frequency of cleavable complexes (Pommier, 1996), thereby increasing DNA damage. As a consequence, DNA single-strand breaks tend to accumulate, and it is most likely that attempts to replicate and/or repair the damaged DNA enhances the formation of DNA double-strand breaks (Vamvakas et al, 1997).…”

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confidence: 99%

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Bras-Gonçalves

Rosty²,

Laurent‐Puig³

et al. 2000

Br J Cancer

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Summary Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI + when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI + and three were MSI -. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg -1 of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-11 (growth delay of up to 10 days); the non-responder tumour was MSI -. At 40 mg kg -1 of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI -/Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI + /wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI + /mutp53) were more sensitive than X17LoVo (MSI + /mutp53. HT 29 tumours (MSI -Imutp53), were refractory to CPT-11 while HT29A3 tumours (MSI -/wtp53) were sensitive, showing that wtp53 improves the drugresponse in these MSI -tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI + being more sensitive than MSI -CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11. © 2000 Cancer Research Campaign Keywords: CPT-11; MSI; p53; top1; human colorectal cancer; nude mice (2000) 82(4), 913-923 © 2000 Cancer Research Campaign DOI: 10.1054/ bjoc.1999.1019, available online at http://www.idealibrary.com on et al, 1998). Cells with functional wtp53 are found to be dramatically more sensitive to many of the commonly used anticancer agents (Fujiwara et al, 1994;Lowe et al, 1993Lowe et al, , 1994McDonald and Brown 1998). In MSI + tumours, defects in mismatch repair genes could lead to the accumulation of unrepaired or misrepaired DNA during DNA replication, rendering them more sensitive for CPT-11 effect.Other resistance mechanisms to CPT-11 could also be implicated. Overexpression of the multidrug resistance gene product, P-glycoprotein, encoded by the mdr1 gene has been incriminated in tumour cell resistance to numerous compounds (Gottesman et al, 1996). Its role in the lack of sensitivity of tumour cells to CPT-11 has been described . Two groups have recently shown that colorectal cancers of the colonic mucosa express the fas receptor (fasR), a cell membrane determinant which triggers the apoptotic casc...

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On the Role of DNA Double-Strand Breaks in Toxicity and Carcinogenesis

Cited by 104 publications

References 115 publications

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

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