Targeting DNA damage response in cancer therapy.
Bottom Line: If the damaged lesions are successfully repaired, the cells will survive.Inhibition of a DNA damage response pathway may enhance the therapeutic effects in combination with the DNA-damaging agents.The most striking application of this strategy is the treatment of cancers deficient in homologous recombination by poly(ADP-ribose) polymerase inhibitors.
Affiliation: Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.Show MeSH
Related in: MedlinePlus
Mentions: The genome DNA is constantly exposed to various genotoxic insults. Among the variety of types of DNA damage, the most deleterious is the DNA double-strand break (DSB).(1) Double-strand breaks can be generated by endogenous sources such as reactive oxygen species produced during cellular metabolic processes and replication-associated errors, as well as by exogenous sources including ionizing radiation and chemotherapeutic agents. Double-strand breaks are also generated in a programmed manner during meiosis and during the V(D)J recombination and class switch recombination required for the development of lymphocytes. If left unrepaired, DSBs can result in cell death. If accurately repaired, DSBs can result in survival of cells with no adverse effects. If insufficiently or inaccurately repaired, DSBs can result in survival of cells showing genomic alterations that may contribute to tumor development.(2) In order to maintain genomic integrity, cells have evolved a well coordinated network of signaling cascades, termed the DNA damage response, to sense and transmit the damage signals to effector proteins, and induce cellular responses including cell cycle arrest, activation of DNA repair pathways, and cell death (Fig. 1).(1)
Affiliation: Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.