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Oxidative DNA damage in neurons: implication of ku in neuronal homeostasis and survival.

De Zio D, Bordi M, Cecconi F - Int J Cell Biol (2012)

Bottom Line: NHEJ directly joins the broken ends, without using the homologous template.Neurons are particularly metabolically active, displaying high rates of transcription and translation, which are associated with high metabolic and mitochondrial activity as well as oxygen consumption.In such a way, excessive oxygen radicals can be generated and constantly attack DNA, thereby producing several lesions.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Dulbecco Telethon Institute, University of Rome "Tor Vergata", Via della Ricerca Scientifica, 00133 Rome, Italy.

ABSTRACT
Oxidative DNA damage is produced by reactive oxygen species (ROS) which are generated by exogenous and endogenous sources and continuously challenge the cell. One of the most severe DNA lesions is the double-strand break (DSB), which is mainly repaired by nonhomologous end joining (NHEJ) pathway in mammals. NHEJ directly joins the broken ends, without using the homologous template. Ku70/86 heterodimer, also known as Ku, is the first component of NHEJ as it directly binds DNA and recruits other NHEJ factors to promote the repair of the broken ends. Neurons are particularly metabolically active, displaying high rates of transcription and translation, which are associated with high metabolic and mitochondrial activity as well as oxygen consumption. In such a way, excessive oxygen radicals can be generated and constantly attack DNA, thereby producing several lesions. This condition, together with defective DNA repair systems, can lead to a high accumulation of DNA damage resulting in neurodegenerative processes and defects in neurodevelopment. In light of recent findings, in this paper, we will discuss the possible implication of Ku in neurodevelopment and in mediating the DNA repair dysfunction observed in certain neurodegenerations.

No MeSH data available.


Related in: MedlinePlus

ROS can generate double-strand breaks with heterogeneous incompatible DNA ends. Following DSB formation, Ku70 and Ku86 form the heterodimer Ku, which can bind directly the two broken DNA termini. Ku, likely changing conformation once it slides onto the DNA end, recruits DNA-PKcs and Artemis to form the DNA-PK complex, which brings the two DNA ends close together and protects them from excessive degradation. DNA-PK phosphorylates itself and also mediates a regulatory phosphorylation of other NHEJ components, such as Artemis. Subsequently, the DNA polymerases (including the pol X polymerases, pol μ and λ) synthetize each DNA segment necessary for the repair. Finally, the DNA-PK complex recruits the LIG4-XRCC4-XLF complex in order to perform the ligation of the DNA termini, after which the DNA-repair factors dissociate.
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fig1: ROS can generate double-strand breaks with heterogeneous incompatible DNA ends. Following DSB formation, Ku70 and Ku86 form the heterodimer Ku, which can bind directly the two broken DNA termini. Ku, likely changing conformation once it slides onto the DNA end, recruits DNA-PKcs and Artemis to form the DNA-PK complex, which brings the two DNA ends close together and protects them from excessive degradation. DNA-PK phosphorylates itself and also mediates a regulatory phosphorylation of other NHEJ components, such as Artemis. Subsequently, the DNA polymerases (including the pol X polymerases, pol μ and λ) synthetize each DNA segment necessary for the repair. Finally, the DNA-PK complex recruits the LIG4-XRCC4-XLF complex in order to perform the ligation of the DNA termini, after which the DNA-repair factors dissociate.

Mentions: Like most DNA repair processes, the NHEJ pathway of DSBs requires three enzymatic activities: (i) nucleases to remove damaged DNA, (ii) polymerases to aid in the repair, and (iii) a ligase to restore the phosphodiester backbone [25]. However, the first step is the recognition of the lesion. Ku is, indeed, deputed to this function. Ku is a heterodimer formed of two subunits: Ku70 and Ku86 (also termed Ku80) [47]. In particular, the complex binds directly the two broken DNA termini so protecting them from excessive degradation and ultimately preparing them for ligation [24]. As shown in Figure 1, the Ku heterodimer is capable of interacting with the nuclease (Artemis-DNA-PKcs) complex, the polymerases (pol μ and pol λ), and the ligase (XLF-XRCC4-DNA Lig IV) complex. Ku first recruits the catalytic subunit of the DNA-PK (DNA-PKcs) and Artemis, this preventing the premature processing of DNA ends, in the repair site [24]. It likely changes conformation once it slides onto the DNA end, since Ku complexes with DNA-PKcs are not detected except when Ku is bound to a DNA end [48]. The new-formed complex (DNA-PK) is able to phosphorylate itself, Artemis, and different substrates. The autophosphorylation causes a conformational change, and DNA-PKcs dissociate from DNA allowing the recruitment of several end-processing enzymes, including XRCC4, DNA Lig IV, and Cernunnos/XLF [23]. The consequence of these activities is the rejoining of DNA ends and the repair of DNA damage. DSBs can also induce the phosphorylation of histone H2AX in the vicinity of DSBs by members of the phosphatidylinositol-3 kinase (PI3K) family, such as DNA-PKcs, ATM, and ATR. This is considered a crucial signal for the cell in order to activate the DNA repair response, since it serves as a site for the accumulation and retention of the central components of the signaling cascade initiated by DNA damage [49].


Oxidative DNA damage in neurons: implication of ku in neuronal homeostasis and survival.

De Zio D, Bordi M, Cecconi F - Int J Cell Biol (2012)

ROS can generate double-strand breaks with heterogeneous incompatible DNA ends. Following DSB formation, Ku70 and Ku86 form the heterodimer Ku, which can bind directly the two broken DNA termini. Ku, likely changing conformation once it slides onto the DNA end, recruits DNA-PKcs and Artemis to form the DNA-PK complex, which brings the two DNA ends close together and protects them from excessive degradation. DNA-PK phosphorylates itself and also mediates a regulatory phosphorylation of other NHEJ components, such as Artemis. Subsequently, the DNA polymerases (including the pol X polymerases, pol μ and λ) synthetize each DNA segment necessary for the repair. Finally, the DNA-PK complex recruits the LIG4-XRCC4-XLF complex in order to perform the ligation of the DNA termini, after which the DNA-repair factors dissociate.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3378965&req=5

fig1: ROS can generate double-strand breaks with heterogeneous incompatible DNA ends. Following DSB formation, Ku70 and Ku86 form the heterodimer Ku, which can bind directly the two broken DNA termini. Ku, likely changing conformation once it slides onto the DNA end, recruits DNA-PKcs and Artemis to form the DNA-PK complex, which brings the two DNA ends close together and protects them from excessive degradation. DNA-PK phosphorylates itself and also mediates a regulatory phosphorylation of other NHEJ components, such as Artemis. Subsequently, the DNA polymerases (including the pol X polymerases, pol μ and λ) synthetize each DNA segment necessary for the repair. Finally, the DNA-PK complex recruits the LIG4-XRCC4-XLF complex in order to perform the ligation of the DNA termini, after which the DNA-repair factors dissociate.
Mentions: Like most DNA repair processes, the NHEJ pathway of DSBs requires three enzymatic activities: (i) nucleases to remove damaged DNA, (ii) polymerases to aid in the repair, and (iii) a ligase to restore the phosphodiester backbone [25]. However, the first step is the recognition of the lesion. Ku is, indeed, deputed to this function. Ku is a heterodimer formed of two subunits: Ku70 and Ku86 (also termed Ku80) [47]. In particular, the complex binds directly the two broken DNA termini so protecting them from excessive degradation and ultimately preparing them for ligation [24]. As shown in Figure 1, the Ku heterodimer is capable of interacting with the nuclease (Artemis-DNA-PKcs) complex, the polymerases (pol μ and pol λ), and the ligase (XLF-XRCC4-DNA Lig IV) complex. Ku first recruits the catalytic subunit of the DNA-PK (DNA-PKcs) and Artemis, this preventing the premature processing of DNA ends, in the repair site [24]. It likely changes conformation once it slides onto the DNA end, since Ku complexes with DNA-PKcs are not detected except when Ku is bound to a DNA end [48]. The new-formed complex (DNA-PK) is able to phosphorylate itself, Artemis, and different substrates. The autophosphorylation causes a conformational change, and DNA-PKcs dissociate from DNA allowing the recruitment of several end-processing enzymes, including XRCC4, DNA Lig IV, and Cernunnos/XLF [23]. The consequence of these activities is the rejoining of DNA ends and the repair of DNA damage. DSBs can also induce the phosphorylation of histone H2AX in the vicinity of DSBs by members of the phosphatidylinositol-3 kinase (PI3K) family, such as DNA-PKcs, ATM, and ATR. This is considered a crucial signal for the cell in order to activate the DNA repair response, since it serves as a site for the accumulation and retention of the central components of the signaling cascade initiated by DNA damage [49].

Bottom Line: NHEJ directly joins the broken ends, without using the homologous template.Neurons are particularly metabolically active, displaying high rates of transcription and translation, which are associated with high metabolic and mitochondrial activity as well as oxygen consumption.In such a way, excessive oxygen radicals can be generated and constantly attack DNA, thereby producing several lesions.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Dulbecco Telethon Institute, University of Rome "Tor Vergata", Via della Ricerca Scientifica, 00133 Rome, Italy.

ABSTRACT
Oxidative DNA damage is produced by reactive oxygen species (ROS) which are generated by exogenous and endogenous sources and continuously challenge the cell. One of the most severe DNA lesions is the double-strand break (DSB), which is mainly repaired by nonhomologous end joining (NHEJ) pathway in mammals. NHEJ directly joins the broken ends, without using the homologous template. Ku70/86 heterodimer, also known as Ku, is the first component of NHEJ as it directly binds DNA and recruits other NHEJ factors to promote the repair of the broken ends. Neurons are particularly metabolically active, displaying high rates of transcription and translation, which are associated with high metabolic and mitochondrial activity as well as oxygen consumption. In such a way, excessive oxygen radicals can be generated and constantly attack DNA, thereby producing several lesions. This condition, together with defective DNA repair systems, can lead to a high accumulation of DNA damage resulting in neurodegenerative processes and defects in neurodevelopment. In light of recent findings, in this paper, we will discuss the possible implication of Ku in neurodevelopment and in mediating the DNA repair dysfunction observed in certain neurodegenerations.

No MeSH data available.


Related in: MedlinePlus