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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

Ku dysfunction can lead to pathological states of the nervous system. Besides NHEJ impairment, which results in DNA damage accumulation, Ku-related alterations of the mitochondrial apoptotic pathway can play a crucial role in neurodevelopment disorders and neoplastic transformations. In particular, Bax-Ku70 and/or Apaf1 promoter-Ku interaction can be decreased and lead to massive apoptosis upon Ku loss of function, as observable in Ku-related disorders of neurodevelopment. Alternatively, Ku gain of function in tumors of the nervous system may lead to an increase of Ku binding to Bax and/or the Apaf1 promoter, thus leading to evade apoptosis and to increase chemoresistance. On the other hand, in a mature nervous system, Ku sequestration mediated by mutant huntingtin can contribute to the HD pathology, by leading to an altered DSBs repair by NHEJ.
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fig2: Ku dysfunction can lead to pathological states of the nervous system. Besides NHEJ impairment, which results in DNA damage accumulation, Ku-related alterations of the mitochondrial apoptotic pathway can play a crucial role in neurodevelopment disorders and neoplastic transformations. In particular, Bax-Ku70 and/or Apaf1 promoter-Ku interaction can be decreased and lead to massive apoptosis upon Ku loss of function, as observable in Ku-related disorders of neurodevelopment. Alternatively, Ku gain of function in tumors of the nervous system may lead to an increase of Ku binding to Bax and/or the Apaf1 promoter, thus leading to evade apoptosis and to increase chemoresistance. On the other hand, in a mature nervous system, Ku sequestration mediated by mutant huntingtin can contribute to the HD pathology, by leading to an altered DSBs repair by NHEJ.

Mentions: The dysfunction of Ku has been demonstrated to have detrimental effects in the nervous system where the NHEJ pathway is the fundamental DSBs repair system used by neurons and where the apoptotic cell death can regulate neural development (Figure 2). For instance, the lack of either Ku70 and/or Ku86 in knockout mice results in dramatic apoptosis of many types of developing embryonic neurons of spinal cord, cerebral cortex, midbrain, and hindbrain [75]. Apoptosis has also been found in the embryonic retina in Ku- animals [76]. Notably, the neuronal apoptosis observed in the Ku70 and Ku86 knockouts is not as severe as in knockouts of the other NHEJ components, and, in fact, the Ku70 and Ku80 knockouts survive into adulthood, even though no apoptosis was found in the nervous system of DNA-PKCS- mice [75]. It has been suggested that neuronal cells might be particularly prone to apoptosis in response to DSBs during neurodevelopment, perhaps in order to eliminate damaged neurons and guarantee a sufficient cell replacement for maintaining neural development [77]. In Ku70−/− mice, migrating cortical neurons, which normally undergo oxidative DNA damage, fail to repair DNA lesion by NHEJ and undergo apoptosis [78]. In addition, it has been demonstrated that the DNA-PK complex, including Ku, can promote survival of young neurons in embryonic mouse retina, thus confirming the critical role of Ku in regulating neurogenesis [79]. In this regard, it has to be also considered that the Ku70/Bax interaction is probably abolished in a Ku-depleted background. This interaction is crucial in regulating the mitochondrial apoptotic pathway by preventing Bax localization into the mitochondria [55–62], and its absence could contribute to the massive apoptosis observed in nervous system of Ku knockout mice. Also, the specific Ku-mediated modulation of the apoptotic gene Apaf1 observed in neural progenitors could account for the excessive cell death observed in Ku-depleted backgrounds [69]. All the above-mentioned processes argue for Ku playing a critical role in neuron survival, either by participating in DSB repair through NHEJ or by regulating apoptosis. According to these assumptions, Ku could also have a role in the chemoresistance of tumors originating from the nervous system (Figure 2). As part of their mechanism of action, most chemotherapeutics affect DNA integrity through the generation of different lesions, such as DSBs. Indeed, it has been reported a correlation between resistance to chemo- and/or radiotherapy and a high Ku70–Ku86 expression/activity [80–82] Moreover, some reports have shown the modulation of Ku70 acetylation status and Ku70-Bax interaction, by means of HDAC inhibitors, both effects inducing chemosensitivity in medulloblastoma and neuroblastoma cells [55, 73, 83]. All this confirms a pivotal role for Ku in neuronal homeostasis and survival.


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)

Ku dysfunction can lead to pathological states of the nervous system. Besides NHEJ impairment, which results in DNA damage accumulation, Ku-related alterations of the mitochondrial apoptotic pathway can play a crucial role in neurodevelopment disorders and neoplastic transformations. In particular, Bax-Ku70 and/or Apaf1 promoter-Ku interaction can be decreased and lead to massive apoptosis upon Ku loss of function, as observable in Ku-related disorders of neurodevelopment. Alternatively, Ku gain of function in tumors of the nervous system may lead to an increase of Ku binding to Bax and/or the Apaf1 promoter, thus leading to evade apoptosis and to increase chemoresistance. On the other hand, in a mature nervous system, Ku sequestration mediated by mutant huntingtin can contribute to the HD pathology, by leading to an altered DSBs repair by NHEJ.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Ku dysfunction can lead to pathological states of the nervous system. Besides NHEJ impairment, which results in DNA damage accumulation, Ku-related alterations of the mitochondrial apoptotic pathway can play a crucial role in neurodevelopment disorders and neoplastic transformations. In particular, Bax-Ku70 and/or Apaf1 promoter-Ku interaction can be decreased and lead to massive apoptosis upon Ku loss of function, as observable in Ku-related disorders of neurodevelopment. Alternatively, Ku gain of function in tumors of the nervous system may lead to an increase of Ku binding to Bax and/or the Apaf1 promoter, thus leading to evade apoptosis and to increase chemoresistance. On the other hand, in a mature nervous system, Ku sequestration mediated by mutant huntingtin can contribute to the HD pathology, by leading to an altered DSBs repair by NHEJ.
Mentions: The dysfunction of Ku has been demonstrated to have detrimental effects in the nervous system where the NHEJ pathway is the fundamental DSBs repair system used by neurons and where the apoptotic cell death can regulate neural development (Figure 2). For instance, the lack of either Ku70 and/or Ku86 in knockout mice results in dramatic apoptosis of many types of developing embryonic neurons of spinal cord, cerebral cortex, midbrain, and hindbrain [75]. Apoptosis has also been found in the embryonic retina in Ku- animals [76]. Notably, the neuronal apoptosis observed in the Ku70 and Ku86 knockouts is not as severe as in knockouts of the other NHEJ components, and, in fact, the Ku70 and Ku80 knockouts survive into adulthood, even though no apoptosis was found in the nervous system of DNA-PKCS- mice [75]. It has been suggested that neuronal cells might be particularly prone to apoptosis in response to DSBs during neurodevelopment, perhaps in order to eliminate damaged neurons and guarantee a sufficient cell replacement for maintaining neural development [77]. In Ku70−/− mice, migrating cortical neurons, which normally undergo oxidative DNA damage, fail to repair DNA lesion by NHEJ and undergo apoptosis [78]. In addition, it has been demonstrated that the DNA-PK complex, including Ku, can promote survival of young neurons in embryonic mouse retina, thus confirming the critical role of Ku in regulating neurogenesis [79]. In this regard, it has to be also considered that the Ku70/Bax interaction is probably abolished in a Ku-depleted background. This interaction is crucial in regulating the mitochondrial apoptotic pathway by preventing Bax localization into the mitochondria [55–62], and its absence could contribute to the massive apoptosis observed in nervous system of Ku knockout mice. Also, the specific Ku-mediated modulation of the apoptotic gene Apaf1 observed in neural progenitors could account for the excessive cell death observed in Ku-depleted backgrounds [69]. All the above-mentioned processes argue for Ku playing a critical role in neuron survival, either by participating in DSB repair through NHEJ or by regulating apoptosis. According to these assumptions, Ku could also have a role in the chemoresistance of tumors originating from the nervous system (Figure 2). As part of their mechanism of action, most chemotherapeutics affect DNA integrity through the generation of different lesions, such as DSBs. Indeed, it has been reported a correlation between resistance to chemo- and/or radiotherapy and a high Ku70–Ku86 expression/activity [80–82] Moreover, some reports have shown the modulation of Ku70 acetylation status and Ku70-Bax interaction, by means of HDAC inhibitors, both effects inducing chemosensitivity in medulloblastoma and neuroblastoma cells [55, 73, 83]. All this confirms a pivotal role for Ku in neuronal homeostasis and survival.

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