The mismatch repair‐mediated cell cycle checkpoint response to fluorodeoxyuridine
- 21 August 2008
- journal article
- research article
- Published by Wiley in Journal of Cellular Biochemistry
- Vol. 105 (1), 245-254
- https://doi.org/10.1002/jcb.21824
Abstract
The loss of DNA mismatch repair (MMR) is responsible for hereditary nonpolyposis colorectal cancer and a subset of sporadic tumors. Acquired resistance or tolerance to some anti‐cancer drugs occurs when MMR function is impaired. 5‐Fluorouracil (FU), an anti‐cancer drug used in the treatment of advanced colorectal and other cancers, and its metabolites are incorporated into RNA and DNA and inhibit thymidylate synthase resulting in depletion of dTTP and incorporation in DNA of uracil. Although the MMR deficiency has been implicated in tolerance to FU, the mechanism of cell killing remains unclear. Here, we examine the cellular response to fluorodeoxyuridine (FdU) and the role of the MMR system. After brief exposure of cells to low doses of FdU, MMR mediates DNA damage signaling during S‐phase and triggers arrest in G2/M in the first cell cycle in a manner requiring MutSα, MutLα, and DNA replication. Cell cycle arrest is mediated by ATR kinase and results in phosphorylation of Chk1 and SMC1. MutSα binds FdU:G mispairs in vitro consistent with its being a DNA damage sensor. Prolonged treatment with FdU results in an irreversible arrest in G2 that is independent of MMR status and leads to the accumulation of DNA lesions that are targeted by the base excision repair (BER) pathway. Thus, MMR can act as a direct sensor of FdU‐mediated DNA lesions eliciting cell cycle arrest via the ATR/Chk1 pathway. However, at higher levels of damage, other damage surveillance pathways such as BER also play important roles. J. Cell. Biochem. 105: 245–254, 2008.This publication has 38 references indexed in Scilit:
- Mismatch repair-dependent processing of methylation damage gives rise to persistent single-stranded gaps in newly replicated DNAGenes & Development, 2007
- 5-Fluorouracil Incorporated into DNA Is Excised by the Smug1 DNA Glycosylase to Reduce Drug CytotoxicityCancer Research, 2007
- Mismatch Repair-dependent Iterative Excision at Irreparable O6-Methylguanine Lesions in Human Nuclear ExtractsPublished by Elsevier BV ,2006
- ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine AdductsMolecular Cell, 2006
- Alterations of DNA damage-response genes ATM and ATR in pyothorax-associated lymphomaLaboratory Investigation, 2005
- Systematic Review of Microsatellite Instability and Colorectal Cancer PrognosisJournal of Clinical Oncology, 2005
- Incorporation of dUMP into DNA is a major source of spontaneous DNA damage, while excision of uracil is not required for cytotoxicity of fluoropyrimidines in mouse embryonic fibroblastsCarcinogenesis: Integrative Cancer Research, 2004
- DNA Mismatch Repair: Molecular Mechanisms and Biological FunctionAnnual Review of Microbiology, 2003
- ATR Is Not Required for p53 Activation but Synergizes with p53 in the Replication CheckpointPublished by Elsevier BV ,2002
- Evidence for AP site formation related to DNA-oxygen alkylation in CHO cells treated with ethylating agentsMutation Research/DNA Repair, 1990