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Targeting DNA damage response in cancer therapy.

Hosoya N, Miyagawa K - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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Early steps of homologous recombination. First, the DNA double-strand break is sensed by the MRE11–RAD50–NBS1 (MRN) complex, which subsequently recruits and activates the ataxia telangiectasia mutated (ATM) kinase. Then, the DNA ends are resected by the MRN complex and CtIP, resulting in generation of 3′ single-stranded DNA (ssDNA) overhangs on both sides of the break. These overhangs are coated and stabilized by replication protein A (RPA). Next, BRCA2, which forms the BRCA1–PALB2–BRCA2 complex, directly binds RAD51 and recruits it to the double-stranded DNA–ssDNA junction, and promotes the loading of RAD51 onto ssDNA. This step is followed by displacement of RPA from ssDNA ends and assembly of the RAD51–ssDNA filament, which is mediated by BRCA2, leading to strand invasion into an undamaged homologous DNA template. All the molecules indicated here are aberrated in sporadic cancers. None of the proteins indicated here are targeted for cancer therapy in the present clinical trials. P, phosphorylation.
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fig02: Early steps of homologous recombination. First, the DNA double-strand break is sensed by the MRE11–RAD50–NBS1 (MRN) complex, which subsequently recruits and activates the ataxia telangiectasia mutated (ATM) kinase. Then, the DNA ends are resected by the MRN complex and CtIP, resulting in generation of 3′ single-stranded DNA (ssDNA) overhangs on both sides of the break. These overhangs are coated and stabilized by replication protein A (RPA). Next, BRCA2, which forms the BRCA1–PALB2–BRCA2 complex, directly binds RAD51 and recruits it to the double-stranded DNA–ssDNA junction, and promotes the loading of RAD51 onto ssDNA. This step is followed by displacement of RPA from ssDNA ends and assembly of the RAD51–ssDNA filament, which is mediated by BRCA2, leading to strand invasion into an undamaged homologous DNA template. All the molecules indicated here are aberrated in sporadic cancers. None of the proteins indicated here are targeted for cancer therapy in the present clinical trials. P, phosphorylation.

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.


Targeting DNA damage response in cancer therapy.

Hosoya N, Miyagawa K - Cancer Sci. (2014)

Early steps of homologous recombination. First, the DNA double-strand break is sensed by the MRE11–RAD50–NBS1 (MRN) complex, which subsequently recruits and activates the ataxia telangiectasia mutated (ATM) kinase. Then, the DNA ends are resected by the MRN complex and CtIP, resulting in generation of 3′ single-stranded DNA (ssDNA) overhangs on both sides of the break. These overhangs are coated and stabilized by replication protein A (RPA). Next, BRCA2, which forms the BRCA1–PALB2–BRCA2 complex, directly binds RAD51 and recruits it to the double-stranded DNA–ssDNA junction, and promotes the loading of RAD51 onto ssDNA. This step is followed by displacement of RPA from ssDNA ends and assembly of the RAD51–ssDNA filament, which is mediated by BRCA2, leading to strand invasion into an undamaged homologous DNA template. All the molecules indicated here are aberrated in sporadic cancers. None of the proteins indicated here are targeted for cancer therapy in the present clinical trials. P, phosphorylation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317796&req=5

fig02: Early steps of homologous recombination. First, the DNA double-strand break is sensed by the MRE11–RAD50–NBS1 (MRN) complex, which subsequently recruits and activates the ataxia telangiectasia mutated (ATM) kinase. Then, the DNA ends are resected by the MRN complex and CtIP, resulting in generation of 3′ single-stranded DNA (ssDNA) overhangs on both sides of the break. These overhangs are coated and stabilized by replication protein A (RPA). Next, BRCA2, which forms the BRCA1–PALB2–BRCA2 complex, directly binds RAD51 and recruits it to the double-stranded DNA–ssDNA junction, and promotes the loading of RAD51 onto ssDNA. This step is followed by displacement of RPA from ssDNA ends and assembly of the RAD51–ssDNA filament, which is mediated by BRCA2, leading to strand invasion into an undamaged homologous DNA template. All the molecules indicated here are aberrated in sporadic cancers. None of the proteins indicated here are targeted for cancer therapy in the present clinical trials. P, phosphorylation.
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.

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.

View Article: PubMed Central - PubMed

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