Role of DNA mismatch repair in apoptotic responses to therapeutic agents

Abstract

Deficiencies in DNA mismatch repair (MMR) have been found in both hereditary cancer (i.e., hereditary nonpolyposis colorectal cancer) and sporadic cancers of various tissues. In addition to its primary roles in the correction of DNA replication errors and suppression of recombination, research in the last 10 years has shown that MMR is involved in many other processes, such as interaction with other DNA repair pathways, cell cycle checkpoint regulation, and apoptosis. Indeed, a cell's MMR status can influence its response to a wide variety of chemotherapeutic agents, such as temozolomide (and many other methylating agents), 6-thioguanine, cisplatin, ionizing radiation, etoposide, and 5-fluorouracil. For this reason, identification of a tumor's MMR deficiency (as indicated by the presence of microsatellite instability) is being utilized more and more as a prognostic indicator in the clinic. Here, we describe the basic mechanisms of MMR and apoptosis and investigate the literature examining the influence of MMR status on the apoptotic response following treatment with various therapeutic agents. Furthermore, using isogenic MMR-deficient (HCT116) and MMR-proficient (HCT116 3-6) cells, we demonstrate that there is no enhanced apoptosis in MMR-proficient cells following treatment with 5-fluoro-2'-deoxyuridine. In fact, apoptosis accounts for only a small portion of the induced cell death response.

Enhanced G2-M Arrest by Nuclear Factor-κB-Dependent p21waf1/cip1 Induction

“…(reviewed in refs. [34][35][36][37]. Induction of p21 waf1/cip1 is also implicated in a G 2 -M arrest in both p53-proficient (38) and p53-deficient (31,39,40) cancer cells.…”

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…The MMR system has been implicated in cell killing by fluoropyrimidines (FPs) as MMRdeficient cells exhibit increased survival after treatment with FdU (Meyers et al, 2004). 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.…”

“…For example, Pani et al (2007) have shown that the MMR pathway contributes to the cytoxicity of cisplatin in human cells; however, other pathways are also critical in mediating the response to cisplatin particularly homologous recombination. In the case of FdU, widely used as an adjuvant therapy in advanced colorectal cancer, MMR-mediated apoptosis (Meyers et al, 2005) may be one of several contributors to the overall cytotoxicity of FdU as base excision repair (BER) enzymes also target FdU (Meyers et al, 2004). The BER enzyme SMUG1 removes FdU from DNA and confers protection from cell killing .…”

Human POLB Gene Is Mutated in High Percentage of Colorectal Tumors

“…Additionally, in hereditary nonpolyposis colon cancer patients, germ line missense mutations have been identified in MMR pathway members, including MLH1, MSH2, and MSH6 (4 -6). Aberrant or reduced levels of MMR can result in defects in apoptosis, leading to resistance to therapy (7,8).…”