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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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Overview of the diverse spectrum of DNA damage and the DNA damage response. The major repair pathways and key proteins used to process each type of damage are shown. In non-homologous end-joining (NHEJ), the Ku70/Ku80 complex binds to the DNA double-strand break ends and recruits the other indicated components. In base-excision repair (BER), poly(ADP-ribose) polymerase-1 (PARP-1) detects and binds to single-strand breaks and ensures accumulation of other repair factors at the breaks. Single-strand breaks containing modified DNA ends are recognized by damage-specific proteins such as apurinic/apyrimidinic endonuclease (APE1), which subsequently recruits Polβ and XRCC1-DNA ligase IIIα to accomplish the repair. All the molecules indicated here are aberrated in sporadic cancers. The proteins targeted for cancer therapy in the present clinical trials are marked with red asterisks. alt-NHEJ, alternative NHEJ; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; FA, Fanconi anemia; HR, homologous recombination; MGMT, O6-methylguanine-DNA methyltransferase; MMR, mismatch repair; MRN, MRE11–RAD50–NBS1; NER, nucleotide excision repair; TLS, translesion synthesis.
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fig01: Overview of the diverse spectrum of DNA damage and the DNA damage response. The major repair pathways and key proteins used to process each type of damage are shown. In non-homologous end-joining (NHEJ), the Ku70/Ku80 complex binds to the DNA double-strand break ends and recruits the other indicated components. In base-excision repair (BER), poly(ADP-ribose) polymerase-1 (PARP-1) detects and binds to single-strand breaks and ensures accumulation of other repair factors at the breaks. Single-strand breaks containing modified DNA ends are recognized by damage-specific proteins such as apurinic/apyrimidinic endonuclease (APE1), which subsequently recruits Polβ and XRCC1-DNA ligase IIIα to accomplish the repair. All the molecules indicated here are aberrated in sporadic cancers. The proteins targeted for cancer therapy in the present clinical trials are marked with red asterisks. alt-NHEJ, alternative NHEJ; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; FA, Fanconi anemia; HR, homologous recombination; MGMT, O6-methylguanine-DNA methyltransferase; MMR, mismatch repair; MRN, MRE11–RAD50–NBS1; NER, nucleotide excision repair; TLS, translesion synthesis.

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)


Targeting DNA damage response in cancer therapy.

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

Overview of the diverse spectrum of DNA damage and the DNA damage response. The major repair pathways and key proteins used to process each type of damage are shown. In non-homologous end-joining (NHEJ), the Ku70/Ku80 complex binds to the DNA double-strand break ends and recruits the other indicated components. In base-excision repair (BER), poly(ADP-ribose) polymerase-1 (PARP-1) detects and binds to single-strand breaks and ensures accumulation of other repair factors at the breaks. Single-strand breaks containing modified DNA ends are recognized by damage-specific proteins such as apurinic/apyrimidinic endonuclease (APE1), which subsequently recruits Polβ and XRCC1-DNA ligase IIIα to accomplish the repair. All the molecules indicated here are aberrated in sporadic cancers. The proteins targeted for cancer therapy in the present clinical trials are marked with red asterisks. alt-NHEJ, alternative NHEJ; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; FA, Fanconi anemia; HR, homologous recombination; MGMT, O6-methylguanine-DNA methyltransferase; MMR, mismatch repair; MRN, MRE11–RAD50–NBS1; NER, nucleotide excision repair; TLS, translesion synthesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig01: Overview of the diverse spectrum of DNA damage and the DNA damage response. The major repair pathways and key proteins used to process each type of damage are shown. In non-homologous end-joining (NHEJ), the Ku70/Ku80 complex binds to the DNA double-strand break ends and recruits the other indicated components. In base-excision repair (BER), poly(ADP-ribose) polymerase-1 (PARP-1) detects and binds to single-strand breaks and ensures accumulation of other repair factors at the breaks. Single-strand breaks containing modified DNA ends are recognized by damage-specific proteins such as apurinic/apyrimidinic endonuclease (APE1), which subsequently recruits Polβ and XRCC1-DNA ligase IIIα to accomplish the repair. All the molecules indicated here are aberrated in sporadic cancers. The proteins targeted for cancer therapy in the present clinical trials are marked with red asterisks. alt-NHEJ, alternative NHEJ; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; FA, Fanconi anemia; HR, homologous recombination; MGMT, O6-methylguanine-DNA methyltransferase; MMR, mismatch repair; MRN, MRE11–RAD50–NBS1; NER, nucleotide excision repair; TLS, translesion synthesis.
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)

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