A concise review of DNA damage checkpoints and repair in mammalian cells.
DNA of eukaryotic cells, including vascular cells, is under the constant attack of chemicals, free radicals, or ionizing radiation that can be caused by environmental exposure, by-products of intracellular metabolism, or medical therapy. Damage may be either limited to altered DNA bases and abasic sites or extensive like double-strand breaks (DSBs). Nuclear proteins sense this damage and initiate the attachment of protein complexes at the site of the lesion. Subsequently, signal transducers, mediators, and finally, effector proteins phosphorylate targets (e.g., p53) that eventually results in cell cycle arrest at the G1/S, intra-S, or G2/M checkpoint until the lesion undergoes repair. Defective cell cycle arrest at the respective checkpoints is associated with genome instability and oncogenesis. When cell cycle arrest is accomplished, the DNA repair machinery can become effective. Important pathways in mammalian cells are the following: base excision repair, nucleotide excision repair, mismatch repair, and DSB repair. When repair is successful, the cell cycle arrest may be lifted. If repair is unsuccessful (e.g., by high doses of DNA-damaging agents or genetic defects in the DNA repair machinery), then this may lead to permanent cell cycle arrest (cellular senescence), apoptosis, or oncogenesis.
Houtgraaf
Jaco H
JH
Department of Cell Biology and Genetics, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Versmissen
Jorie
J
van der Giessen
Wim J
WJ
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005057:Eukaryotic Cells / Q000166:cytology / Q000473:pathology*; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011494:Protein Kinases