Hypersensitivity in DNA mismatch repair-deficient colon carcinoma cells to DNA polymerase reaction inhibitors

Takahashi, T.; Min, Zhenghua; Uchida, Iichiro; Arita, Michitsune; Watanabe, Yoh; Koi, Minoru; Hemmi, Hiromichi

doi:10.1016/j.canlet.2004.07.044

Cited by 17 publications

(22 citation statements)

References 19 publications

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“…Our data on chromosomal damage provoked by APC reflect a higher sensitivity to the anti-proliferative effects (evaluated by clonogenic assay) of APC and other DNA polymerases inhibitors that was previously reported in MMR-deficient colon cancer cell lines, including HCT-116 derived cells [47]. Moreover, long-term primary cultures of fibroblasts derived from MSH2 −/− mice are known to have elevated induction of gaps and breaks after exposure to APC indicating that proteins involved in MMR could be implicated in CFS stability [48].…”

Section: Discussionsupporting

confidence: 77%

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

Vernole

Muzi

Volpi

et al. 2011

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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t r a c tCommon fragile sites (CFS) are specific chromosomal areas prone to form gaps and breaks when cells are exposed to stresses that affect DNA synthesis, such as exposure to aphidicolin (APC), an inhibitor of DNA polymerases. The APC-induced DNA damage is repaired primarily by homologous recombination (HR), and RAD51, one of the key players in HR, participates to CFS stability. Since another DNA repair pathway, the mismatch repair (MMR), is known to control HR, we examined the influence of both the MMR and HR DNA repair pathways on the extent of chromosomal damage and distribution of CFS provoked by APC and/or by RAD51 silencing in MMR-deficient and -proficient colon cancer cell lines (i.e., HCT-15 and HCT-15 transfected with hMSH6, or HCT-116 and HCT-116/3+6, in which a part of a chromosome 3 containing the wild-type hMLH1 allele was inserted). Here, we show that MMR-deficient cells are more sensitive to APC-induced chromosomal damage particularly at the CFS as compared to MMR-proficient cells, indicating an involvement of MMR in the control of CFS stability. The most expressed CFS is FRA16D in 16q23, an area containing the tumour suppressor gene WWOX often mutated in colon cancer. We also show that silencing of RAD51 provokes a higher number of breaks in MMR-proficient cells with respect to their MMR-deficient counterparts, likely as a consequence of the combined inhibitory effects of RAD51 silencing on HR and MMR-mediated suppression of HR. The RAD51 silencing causes a broader distribution of breaks at CFS than that observed with APC. Treatment with APC of RAD51-silenced cells further increases DNA breaks in MMR-proficient cells. The RNAi-mediated silencing of PARP-1 does not cause chromosomal breaks or affect the expression/distribution of CFS induced by APC. Our results indicate that MMR modulates colon cancer sensitivity to chromosomal breaks and CFS induced by APC and RAD51 silencing.

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Section: Discussionsupporting

confidence: 77%

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

Vernole

Muzi

Volpi

et al. 2011

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…MMR gene mutations or epigenetic silencing is found in a variety of hereditary and sporadic cancers (10,18,39). MMR gene defects are associated with decreased sensitivity to DNA damaging drugs, such as cisplatin, doxorubicin, and 5-fluorouracil (13,17), but show increased sensitivity to agents that disrupt DNA replication by inhibition of DNA polymerase (60). In our system, where DNA replication is stalled during S phase, followed by ROS-induced DNA damage, these defects may have some role in the baseline apoptosis seen in cells proficient in Chk2.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage during Reoxygenation Elicits a Chk2-Dependent Checkpoint Response

Freiberg

Hammond

Dorie

et al. 2006

Molecular and Cellular Biology

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Due to the abnormal vasculature of solid tumors, tumor cell oxygenation can change rapidly with the opening and closing of blood vessels, leading to the activation of both hypoxic response pathways and oxidative stress pathways upon reoxygenation. Here, we report that ataxia telangiectasia mutated-dependent phosphorylation and activation of Chk2 occur in the absence of DNA damage during hypoxia and are maintained during reoxygenation in response to DNA damage. Our studies involving oxidative damage show that Chk2 is required for G 2 arrest. Following exposure to both hypoxia and reoxygenation, Chk2 ؊/؊ cells exhibit an attenuated G 2 arrest, increased apoptosis, reduced clonogenic survival, and deficient phosphorylation of downstream targets. These studies indicate that the combination of hypoxia and reoxygenation results in a G 2 checkpoint response that is dependent on the tumor suppressor Chk2 and that this checkpoint response is essential for tumor cell adaptation to changes that result from the cycling nature of hypoxia and reoxygenation found in solid tumors.

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“…6 Similarly, there is some evidence that DNA MMR components might also have a role in modulating in vitro response to gemcitabine, a nucleoside analog of deoxycytidine also used to treat leukemia. Notably, Takahashi et al 7 reported gemcitabine to be more toxic to hMLH1-deficient cells than their MMR-proficient counterparts. Although these data suggest involvement of DNA MMR components in response to nucleoside analogs, they do not confirm a role for the DNA MMR pathway per se, as response could be mediated through other pathways in which MMR components participate, as we have suggested.…”

Section: Letters To the Editormentioning

confidence: 99%

DNA mismatch repair status affects cellular response to Ara-C and other anti-leukemic nucleoside analogs

et al. 2011

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Hypersensitivity in DNA mismatch repair-deficient colon carcinoma cells to DNA polymerase reaction inhibitors

Cited by 17 publications

References 19 publications

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

DNA Damage during Reoxygenation Elicits a Chk2-Dependent Checkpoint Response

DNA mismatch repair status affects cellular response to Ara-C and other anti-leukemic nucleoside analogs

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