Hypersensitivity to camptothecin in MSH2 deficient cells is correlated with a role for MSH2 protein in recombinational repair

Pichierri, Pietro; Franchitto, Annapaola; Piergentili, Rita; Colussi, Claudia; Palitti, F.

doi:10.1093/carcin/22.11.1781

Cited by 38 publications

(25 citation statements)

References 41 publications

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“…Cells lacking the mismatch repair protein, MSH2, are hypersensitive to CPT (Pichierri et al, 2001). Recently, Meijer et al (2002) showed that a eucaryotic polynucleotide kinase, Pnk1, also plays a role in CPT-induced DNA damage repair, and cells lacking this gene are hypersensitive to CPT.…”

Section: Alterations In the Cellular Response To Ternary Complex Formmentioning

confidence: 99%

Mechanisms of resistance to topoisomerase I-targeting drugs

Rasheed¹,

Rubin²

2003

Oncogene

155

130

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Section: Alterations In the Cellular Response To Ternary Complex Formmentioning

confidence: 99%

Mechanisms of resistance to topoisomerase I-targeting drugs

Rasheed¹,

Rubin²

2003

Oncogene

155

130

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“…All the cell lines were cultured and handled as already described (Pichierri et al , 2001). For biochemical analyses, cells were enriched in late-S/G2 prior to X-ray irradiation by a double thymidine block.…”

Section: Cell Cultures and Synchronizationmentioning

confidence: 99%

“…In order to analyse MRE11 foci in untreated or irradiated cells shortly after treatment, fixation in a 4% paraformaldehyde-buffered solution was carried out after an in situ fractionation procedure as described (Mirzoeva and Petrini, 2001). Cells were then immediately processed, as previously described (Pichierri et al, 2001), for immunochemical detection of MRE11 or RAD51 using rabbit polyclonal anti-RAD51 or MRE11 antibodies (Oncogene Research) and Alexa546-conjugated mouse anti-rabbit secondary antibody (Molecular Probes). Alternatively, irradiated cultures were processed for simultaneous visualization of RAD51 foci and human proliferating cell nuclear antigen (PCNA) (Santa Cruz Biotechnology).…”

Section: Analysis Of Mre11 and Rad51 Focimentioning

confidence: 99%

“…While the role of MMR in the correction of replication errors is well established, its involvement in the processing of DNA damage induced by chemical and physical agents is less clear. Thus, whereas inactivation of MMR always leads to tolerance to methylating agents (Karran and Bignami, 1994), either moderate levels of resistance (Aebi et al, 1996;Anthoney et al, 1996) or hypersensitivity to other types of DNA damage has been observed in MMR-defective cells (Fiumicino et al, 2000;Pichierri et al, 2001). For example, MSH2 À/À , MLH1 À/À and PMS2 À/À mouse embryo fibroblasts (MEFs) show a modest increase in survival compared to wild-type cells after exposure to ionizing radiation (IR), while conflicting results were observed in other human cellular models Davis et al, 1998;DeWeese et al, 1998;Fritzell et al, 1997;Xu et al, 2001b;Zeng et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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The mammalian mismatch repair protein MSH2 is required for correct MRE11 and RAD51 relocalization and for efficient cell cycle arrest induced by ionizing radiation in G2 phase

et al. 2003

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In yeast, MSH2 plays an important role in mismatch repair (MMR) and recombination, whereas the function of the mammalian MSH2 protein in recombinational repair is not completely established. We examined the cellular responses of MSH2-deficient mouse cells to X-rays to clarify the role of MSH2 in recombinational repair. Cell survival, checkpoint functions and relocalization of the recombination-related proteins MRE11 and RAD51 were analysed in embryonic fibroblasts derived from MSH2 +/+ and MSH2 À/À mice, and in MSH2-proficient and deficient mouse colorectal carcinoma cells. Loss of MSH2 function was found to be associated with reduction in cell survival following radiation, absence of either MRE11 or RAD51 relocalization and a higher level of X-ray-induced chromosomal damage specifically in G2-phase cells. Finally, MSH2 À/À cells showed an inefficient early G2/M checkpoint, being arrested only transiently after irradiation before progressing into mitosis. Consistent with the premature release from the G2-phase arrest, activation of CHK1 was transient and CHK2 was not phosphorylated in synchronized MSH2-null cells. Our data suggest that an active MSH2 is required for a correct response to ionizing radiation-induced DNA damage in the G2 phase of the cell cycle, possibly connecting DSB repair to checkpoint signalling.

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“…In particular, MMR is required for the cytotoxic activity of a variety of anticancer agents, including methylating compounds, 6-thioguanine and cisplatin [13]. It has been recently demonstrated that MMR inhibits HR likely by aborting strand exchanges between homeologous (i.e., not completely homologous) sequences [14][15][16][17][18]. Furthermore, the complex hMSH2/hMSH6 has been shown to bind to Holliday junctions and to play a direct role in HR [19].…”

Section: Introductionmentioning

confidence: 99%

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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Hypersensitivity to camptothecin in MSH2 deficient cells is correlated with a role for MSH2 protein in recombinational repair

Cited by 38 publications

References 41 publications

Mechanisms of resistance to topoisomerase I-targeting drugs

Mechanisms of resistance to topoisomerase I-targeting drugs

The mammalian mismatch repair protein MSH2 is required for correct MRE11 and RAD51 relocalization and for efficient cell cycle arrest induced by ionizing radiation in G2 phase

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

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