A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage

Meyers, Mark; Hwang, Arlene; Wagner, Mark W.; Bruening, A.; Veigl, Martina L.; Sedwick, W. David; Boothman, David A.

doi:10.1038/sj.onc.1206941

Cited by 62 publications

(69 citation statements)

References 127 publications

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“…In this regard, it has recently become evident that MMR-deficient tumors are often resistant to treatment with 5-FU, the first-line standard therapeutic for colorectal cancer (Ragnhammar et al, 2001), a clinical feature that is consistent with the phenotype displayed by the same type of cancer cells in culture (Meyers et al, 2001;Arnold et al, 2003;Ju et al, 2007;Wang et al, 2007). Indeed, it has been shown that the MMR system plays a prominent role in the detection and removal of fluoropyrimidine-induced lesions (Meyers et al, 2001;Meyers et al, 2003Meyers et al, , 2005. The exact mechanism between loss of MMR and chemoresistance is not completely understood, although it is known that MMR-deficient cells can tolerate a higher level of DNA damage induced by 5-FU, an observation confirmed by our studies.…”

Section: Discussionmentioning

confidence: 99%

Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair–deficient Colorectal Cancer Cells

Jardim¹,

Wang²,

Furumai³

et al. 2009

MBoC

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Genomic instability in colorectal cancer is categorized into two distinct classes: chromosome instability (CIN) and microsatellite instability (MSI). MSI is the result of mutations in the mismatch repair (MMR) machinery, whereas CIN is often thought to be associated with a disruption in the APC gene. Clinical data has recently shown the presence of heterozygous mutations in ATR and Chk1 in human cancers that exhibit MSI, suggesting that those mutations may contribute to tumorigenesis. To determine whether reduced activity in the DNA damage checkpoint pathway would cooperate with MMR deficiency to induce CIN, we used siRNA strategies to partially decrease the expression of ATR or Chk1 in MMR-deficient colorectal cancer cells. The resultant cancer cells display a typical CIN phenotype, as characterized by an increase in the number of chromosomal abnormalities. Importantly, restoration of MMR proficiency completely inhibited induction of the CIN phenotype, indicating that the combination of partial checkpoint blockage and MMR deficiency is necessary to trigger CIN. Moreover, disruption of ATR and Chk1 in MMR-deficient cells enhanced the sensitivity to treatment with the commonly used colorectal chemotherapeutic compound, 5-fluorouracil. These results provide a basis for the development of a combination therapy for those cancer patients. INTRODUCTIONEukaryotic cells are continuously exposed to endogenous and exogenous insults capable of damaging DNA. To maintain the integrity of their genomes, cells have evolved a series of sophisticated and complex signaling networks that allow cells to respond to genotoxic injury. Such responses include recognition of DNA lesions, activation of cell cycle checkpoints and DNA repair mechanisms, and, in the event of irreparable damage, initiation of apoptosis. Defects in many of these surveillance mechanisms result in the inability of cells to properly process genomic stresses, often leading to genomic instability and subsequently tumorigenesis. Genomic instability can be divided into two clinically distinct classes that have been extensively studied in colorectal cancers: chromosome instability (CIN) and microsatellite instability (MSI) (Kinzler and Vogelstein, 1996;Harfe and Jinks-Robertson, 2000;Rajagopalan et al., 2003;Rustgi, 2007). Tumors with CIN comprise ϳ85% of all colorectal cancers and are characterized by gross karyotypic changes exhibiting abnormalities in chromosome structure and number (Rajagopalan et al., 2003). The pathway leading to the development of CIN is not currently clear but it has been correlated with truncations in the adenomatous polyposis coli (APC) protein (Kinzler and Vogelstein, 1996;Rajagopalan et al., 2003). Tumors with MSI account for the remaining 15% of colorectal cancers. In contrast to CIN tumors, MSI tumors have a relatively stable karyotype and harbor anomalies at the nucleotide level, resulting in frameshift and missense mutations that disrupt the normal function of proto-oncogenes and tumor suppressors. This type of instability has been dir...

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Section: Discussionmentioning

confidence: 99%

Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair–deficient Colorectal Cancer Cells

Jardim¹,

Wang²,

Furumai³

et al. 2009

MBoC

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“…Arrest in G2 is observed within the first cell cycle in MMR-proficient cells, but not in MMR-deficient cells (Carethers et al, 1999;Meyers et al, 2003Meyers et al, , 2005. Inhibition of TS without FU treatment elicits a G2 arrest regardless of MMR status suggesting that the contribution of MMR to DNA damage signalling is via incorporation of FPs into DNA as opposed to the inhibition of TS and the resulting imbalance in nucleotide pools.…”

Section: Mmr and Dna Damage Signallingmentioning

confidence: 95%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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“…Fluorodeoxyuridine monophosphate is also converted into fluorodeoxyuridine triphosphate (FdUTP) which itself is a substrate for DNA polymerases and readily misincorporated into DNA (Sampath et al, 2003). FdUTP or dUTP misincorporation is potentially mutagenic and miscoding, however, both can be excised through the action of base excision repair (BER) (Ingraham et al, 1980;Mauro et al, 1993) and, in the case of FdUTP, potentially mismatch repair (MMR) (Meyers et al, 2001(Meyers et al, , 2005Tajima et al, 2004). Finally, conversion of 5FU to fluorouridine triphosphate allows incorporation into both messenger and structural RNAs with potentially deleterious effects on stability, processing, modification, and coding potential (Longley et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil

et al. 2006

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Chk1 plays a crucial role in the DNA damage and replication checkpoints in vertebrates and may therefore be an important determinant of tumour cell responses to genotoxic anticancer drugs. To evaluate this concept we compared the effects of the nucleoside analogue 5-fluorouracil (5FU) on cell cycle progression and clonogenic survival in DT40 B-lymphoma cells with an isogenic mutant derivative in which Chk1 function was ablated by gene targeting. We show that 5FU activates Chk1 in wild-type DT40 cells and that 5FU-treated cells accumulate in the S phase of the cell cycle due to slowing of the overall rate of DNA replication. In marked contrast, Chk1-deficient DT40 cells fail to slow DNA replication upon initial exposure to 5FU, despite equivalent inhibition of the target enzyme thymidylate synthase, and instead accumulate progressively in the G1 phase of the following cell cycle. This G1 accumulation cannot be reversed rapidly by exogenous thymidine or removal of 5FU, and is associated with increased incorporation of 5FU into genomic DNA and severely diminished clonogenic survival. Taken together, these results demonstrate that a Chk1-dependent replication checkpoint which slows S phase progression can protect tumour cells against the cytotoxic effects of 5FU.

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A role for DNA mismatch repair in sensing and responding to fluoropyrimidine damage

Cited by 62 publications

References 127 publications

Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair–deficient Colorectal Cancer Cells

Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair–deficient Colorectal Cancer Cells

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil

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