Mammalian DNA mismatch repair protects cells from UVB-induced DNA damage by facilitating apoptosis and p53 activation

Peters, Anthea; Young, Leah C.; Maeda, Tomoko; Tron, Victor A.; Andrew, Susan E.

doi:10.1016/s1568-7864(03)00003-x

Cited by 52 publications

(46 citation statements)

References 36 publications

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“…in the clonogenic survival assay we have also shown significantly enhanced survival of MS5-7 cells compared to BC1-6 cells. Similar results have been reported for these cell lines in response to ionizing radiation (22,30). Taken together, these results suggest that elevated NeR contributes to cisplatin resistance in MS5-7 cells.…”

Section: Host Cell Reactivation and Mtt Reduction Capacity In Msh2-desupporting

confidence: 90%

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A combination of MSH2 DNA mismatch repair deficiency and expression of the SV40 large T antigen results in cisplatin resistance of mouse embryonic fibroblasts

Yasin

Rainbow

2011

Int J Oncol

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Abstract. Mutations in the human mismatch repair (MMR) genes are associated with hereditary non-polyposis colorectal cancer as well as other sporadic cancers. MMR gene mutations have been implicated in the resistance of human tumours to cisplatin and several tumour-derived MMR-deficient cells show cisplatin resistance in vitro. In addition, hypoxia, a common feature of the tumour microenvironment, has been shown to influence tumour responses to conventional cancer treatments. We have examined the role of the mMSH2 MMR protein on repair of cisplatin-damaged DNA and cisplatin sensitivity in mMSH2-deficient murine fibroblasts and mMSH2-proficient controls under conditions of normoxia and hypoxia. Sensitivity to cisplatin was measured using the MTT assay and clonogenic survival. Repair of cisplatin-damaged DNA was measured using a host cell reactivation (HCR) assay employing a non-replicating recombinant virus expressing the β-galactosidase reporter gene. Sensitivity to cisplatin was significantly less and HCR of the cisplatin-damaged reporter gene was significantly greater in SV40-transformed mMSH2-deficient cells (MS5-7) compared to mMSH2-proficient controls (BC1-6) under both normoxic and hypoxic conditions. In contrast, sensitivity to cisplatin was significantly greater and HCR was similar in primary mMSH2-deficient compared to mMSH2-proficient murine fibroblasts under both normoxic and hypoxic conditions. Sensitivity to cisplatin was also significantly greater and HCR was similar in primary mMSH2-deficient compared to mMSH2-proficient murine fibroblasts transfected with a control plasmid under both normoxic and hypoxic conditions. In contrast, sensitivity to cisplatin was less and HCR was similar in primary mMSH2-deficient compared to mMSH2-proficient murine fibroblasts transfected with a plasmid expressing SV40 large T antigen under both normoxic and hypoxic conditions. These results suggest that loss of MMR alone does not result in increased resistance to cisplatin in murine fibroblasts and that additional concomitant alterations in cells expressing the SV40 large T antigen are responsible for cisplatin resistance through a modulation of DNA repair capacity and/or apoptosis.

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Section: Host Cell Reactivation and Mtt Reduction Capacity In Msh2-desupporting

confidence: 90%

“…It has been suggested that the MSH2 gene product protects cells from tumourigenesis by facilitating apoptosis and p53 activation (30). Therefore, another possible change leading to increased cisplatin resistance in the large T antigen-expressing mMSH2-deficient cells is reduced apoptosis.…”

Section: Host Cell Reactivation and Mtt Reduction Capacity In Msh2-dementioning

confidence: 99%

A combination of MSH2 DNA mismatch repair deficiency and expression of the SV40 large T antigen results in cisplatin resistance of mouse embryonic fibroblasts

Yasin

Rainbow

2011

Int J Oncol

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“…In response to UVB, 15 to 25% of wild-type MEFs undergo apoptosis at the dose of 100 J/m 2 , correlating with previous reports. 37 This percentage increased from 28 to 63% when these cells were treated with a higher dose (Fig. 4A and S3a).…”

Section: Mice Homozygous For P53mentioning

confidence: 91%

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence

et al. 2010

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“…In particular, MMR proteins have been directly involved in signaling DNA damage through the p53 pathway (Duckett et al, 1999;Peters et al, 2003;Luo et al, 2004). To address whether the rescue of proliferation defects and aging pathologies in G1-G3 Terc -/-/MSH2 -/-mice could be due to a role for MSH2 in signaling telomere dysfunction through the p53-p21 cellular senescence axis, we determined p53 and p21 levels by immunohistochemistry directly on small intestine sections (Experimental procedures).…”

Section: Msh2 Deficiency Results In An Attenuated P53 and P21 Inductimentioning

confidence: 99%

“…Mice deficient in different MMR genes, as well as in EXO1, show an increase in both the spontaneous mutation rates and susceptibility to develop cancer; the MSH2 knockout mouse having the most severe cancer-prone phenotype (Baker et al ., 1995;de Wind et al ., 1995;Prolla et al ., 1998;Wei et al ., 2003). A role for MMR proteins in signaling DNA damage by direct involvement of the p53 pathway has also been proposed (Duckett et al ., 1999;Peters et al ., 2003;Luo et al ., 2004), which in turn could affect tumorigenesis. Additionally, MMR factors activate ataxia telangiectasia mutated (ATM) signaling in the S-phase checkpoint response to DNA damage (Brown et al ., 2003).…”

Section: Introductionmentioning

confidence: 99%

MSH2 deficiency abolishes the anticancer and pro‐aging activity of short telomeres

et al. 2009

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SummaryMutations in the mismatch repair (MMR) pathway occur in human colorectal cancers with microsatellite instability. Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, including telomere shortening, is a potent anticancer barrier. The telomerase-deficient mouse model illustrates the anticancer effect of cell-cycle arrest provoked by short telomeres. Here, we describe a role for the MMR protein, MSH2, in signaling cell-cycle arrest in a p21/p53-dependent manner in response to short telomeres in the context of telomerasedeficient mice. In particular, progressively shorter telomeres at successive generations of MSH2 -/-Terc -/--mice did not suppress cancer in these mice, indicating that MSH2 deficiency abolishes the tumor suppressor activity of short telomeres. Interestingly, MSH2 deficiency prevented degenerative pathologies in the gastrointestinal tract of MSH2 -/-Terc -/-mice concomitant with a rescue of proliferative defects. The abolishment of the anticancer and pro-aging effects of short telomeres provoked by MSH2 abrogation was independent of changes in telomere length. These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway.

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Mammalian DNA mismatch repair protects cells from UVB-induced DNA damage by facilitating apoptosis and p53 activation

Cited by 52 publications

References 36 publications

A combination of MSH2 DNA mismatch repair deficiency and expression of the SV40 large T antigen results in cisplatin resistance of mouse embryonic fibroblasts

A combination of MSH2 DNA mismatch repair deficiency and expression of the SV40 large T antigen results in cisplatin resistance of mouse embryonic fibroblasts

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence

MSH2 deficiency abolishes the anticancer and pro‐aging activity of short telomeres

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