Mismatch repair and DNA damage signalling.
Postreplicative mismatch repair (MMR) increases the fidelity of DNA replication by up to three orders of magnitude, through correcting DNA polymerase errors that escaped proofreading. MMR also controls homologous recombination (HR) by aborting strand exchange between divergent DNA sequences. In recent years, MMR has also been implicated in the response of mammalian cells to DNA damaging agents. Thus, MMR-deficient cells were shown to be around 100-fold more resistant to killing by methylating agents of the S(N)1type than cells with functional MMR. In the case of cisplatin, the sensitivity difference was lower, typically two- to three-fold, but was observed in all matched MMR-proficient and -deficient cell pairs. More controversial is the role of MMR in cellular response to other DNA damaging agents, such as ionizing radiation (IR), topoisomerase poisons, antimetabolites, UV radiation and DNA intercalators. The MMR-dependent DNA damage signalling pathways activated by the above agents are also ill-defined. To date, signalling cascades involving the Ataxia telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), as well as the stress-activated kinases JNK/SAPK and p38alpha have been linked with methylating agent and 6-thioguanine (TG) treatments, while cisplatin damage was reported to activate the c-Abl and JNK/SAPK kinases in MMR-dependent manner. MMR defects are found in several different cancer types, both familiar and sporadic, and it is possible that the involvement of the MMR system in DNA damage signalling play an important role in transformation. The scope of this article is to provide a brief overview of the recent literature on this subject and to raise questions that could be addressed in future studies.
Institute of Molecular Cancer Research, University of Zurich, August Forel-Strasse 7, 8008 Zurich, Switzerland.
Lovorka
L
Stojic
Richard
R
Brun
Josef
J
Jiricny
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D020137:Base Pair Mismatch; D018797:Cell Cycle Proteins / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000648:ultrastructure; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011839:Radiation, Ionizing; D011995:Recombination, Genetic; D015398:Signal Transduction; D013866:Thioguanine / Q000737:chemistry; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D004259:DNA-Directed DNA Polymerase; D013866:Thioguanine; D002945:Cisplatin