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 DNA repair pathways can either work independently or coordinately to repair different types of DNA damage (Fig. 1). Double-strand breaks are predominantly repaired by either NHEJ or homologous recombination (HR).(10) Non-homologous end joining is an error-prone repair pathway that is mediated by the direct joining of the two broken ends.(10) Factors involved in NHEJ include the Ku70/Ku80 complex, DNA-PK catalytic subunit (DNA-PKcs), the Artemis nuclease, XLF, XRCC4, and DNA ligase IV. Homologous recombination is an error-free repair pathway that requires a non-damaged sister chromatid to serve as a template for repair (Fig. 2).(10) Factors involved in HR include the MRN complex, CtIP, replication protein A (RPA), BRCA1, PALB2, BRCA2, and RAD51. In addition to NHEJ and HR, an alternative form of NHEJ, namely, alt-NHEJ, is also involved in DSB repair.(11) It exhibits a slower process than the classical NHEJ and can catalyze the joining of unrelated DNA molecules, leading to the formation of translocations as well as large deletions and other sequence alterations at the junction. Factors involved in this pathway include PARP-1, XRCC1, DNA ligase IIIα, polynucleotide kinase, and Flap endonuclease 1.
Affiliation: Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.