The DNA damage response (DDR) is a cellular mechanism that senses, signals and coordinates the assembly of repair factors at the damaged DNA sites. Efficient DDR processes are central to cellular viability and defects in these mechanisms are associated with several sporadic as well as familial genetic diseases in humans. The Brain is composed of both dividing (neural stem cells, astrocytes, glia and endothelial cells) and non-dividing (post-mitotic neurons) cells. Although there has been a great debate on the actual lifespan of a terminally differentiated neuron, scientists now believe that under normal physiological conditions, post-mitotic neurons (e.g., motor neurons) can live as long as the body that contains them lives. Indeed, the loss of neurons is one of the critical pathological hallmarks of most common neurodegenerative diseases. Given this fact, it is understood that post-mitotic neurons possess a highly complex and high-fidelity genome maintenance capacity that allows them to tackle persistent genomic insults during this long lifespan. Among the various types of genome damages, DNA double-strand break (DSB) remains the most lethal one, which has been found to induce a number of cell death mechanisms, including hyper-inflammatory responses, neuronal apoptosis, senescence, forced re-entry into abortive cell cycle, among others.
Recent findings have highlighted the fact that DNA DSBs can not only originate as secondary DSBs from staggered single-strand breaks (SSBs) or directly by exogenous DNA damaging agents, but also form due to activity-induced neuronal gene expressions under normal physiological conditions. Therefore, the question arises, how do neurons survive with so many genomic insults? The answer lies in the fine balance between the extent of DNA damage and the efficiency of the respective repair pathway, which normally declines with ageing. In post-mitotic neurons, non-homologous end joining (NHEJ)-mediated DNA DSB repair is the predominant repair mechanism. Increasingly, DDR signaling dysfunctions and defective DNA DSB repair processes have been implicated in almost all neurodegenerative disorders. It is still unclear how the defect in different repair factors, identified as pathogenic in different neurodegenerative diseases, converges to persistent accumulation of unrepaired DNA DSBs beyond the threshold level of neuronal survival.
So far, much of our knowledge of DNA repair mechanisms has been obtained from studies on both mitotic and post-mitotic cells. However, recent findings have challenged our understanding of DNA damage repair mechanisms in post-mitotic neurons, suggesting that DNA repair processes in these cells are far more complex than originally thought. This includes the recent discovery of the homology directed repair mechanism, which was previously considered to be a DNA repair pathway specific to mitotic cells but is also present in post-mitotic neurons. This research topic will focus on these underexplored areas; both the normal physiological role of the DDR in post-mitotic neurons and how this is compromised in aging and neurodegenerative diseases.
We welcome contributions that explore DDR signaling and its association with various cell survival and death mechanisms in neurons. This may include, but not limited to, topics related to:
1) The DNA damage response in neurons and other brain cells
2) The relationship between cellular metabolism and DNA damage in neurons
3) The relationship between DDR signaling and neuro-inflammation, apoptosis and senescence
4) Perturbed coordination between DDR and DSB repair processes, leading to pathogenic mutations
5) The implications of defective DNA repair mechanisms in neurodegenerative diseases and aging
The DNA damage response (DDR) is a cellular mechanism that senses, signals and coordinates the assembly of repair factors at the damaged DNA sites. Efficient DDR processes are central to cellular viability and defects in these mechanisms are associated with several sporadic as well as familial genetic diseases in humans. The Brain is composed of both dividing (neural stem cells, astrocytes, glia and endothelial cells) and non-dividing (post-mitotic neurons) cells. Although there has been a great debate on the actual lifespan of a terminally differentiated neuron, scientists now believe that under normal physiological conditions, post-mitotic neurons (e.g., motor neurons) can live as long as the body that contains them lives. Indeed, the loss of neurons is one of the critical pathological hallmarks of most common neurodegenerative diseases. Given this fact, it is understood that post-mitotic neurons possess a highly complex and high-fidelity genome maintenance capacity that allows them to tackle persistent genomic insults during this long lifespan. Among the various types of genome damages, DNA double-strand break (DSB) remains the most lethal one, which has been found to induce a number of cell death mechanisms, including hyper-inflammatory responses, neuronal apoptosis, senescence, forced re-entry into abortive cell cycle, among others.
Recent findings have highlighted the fact that DNA DSBs can not only originate as secondary DSBs from staggered single-strand breaks (SSBs) or directly by exogenous DNA damaging agents, but also form due to activity-induced neuronal gene expressions under normal physiological conditions. Therefore, the question arises, how do neurons survive with so many genomic insults? The answer lies in the fine balance between the extent of DNA damage and the efficiency of the respective repair pathway, which normally declines with ageing. In post-mitotic neurons, non-homologous end joining (NHEJ)-mediated DNA DSB repair is the predominant repair mechanism. Increasingly, DDR signaling dysfunctions and defective DNA DSB repair processes have been implicated in almost all neurodegenerative disorders. It is still unclear how the defect in different repair factors, identified as pathogenic in different neurodegenerative diseases, converges to persistent accumulation of unrepaired DNA DSBs beyond the threshold level of neuronal survival.
So far, much of our knowledge of DNA repair mechanisms has been obtained from studies on both mitotic and post-mitotic cells. However, recent findings have challenged our understanding of DNA damage repair mechanisms in post-mitotic neurons, suggesting that DNA repair processes in these cells are far more complex than originally thought. This includes the recent discovery of the homology directed repair mechanism, which was previously considered to be a DNA repair pathway specific to mitotic cells but is also present in post-mitotic neurons. This research topic will focus on these underexplored areas; both the normal physiological role of the DDR in post-mitotic neurons and how this is compromised in aging and neurodegenerative diseases.
We welcome contributions that explore DDR signaling and its association with various cell survival and death mechanisms in neurons. This may include, but not limited to, topics related to:
1) The DNA damage response in neurons and other brain cells
2) The relationship between cellular metabolism and DNA damage in neurons
3) The relationship between DDR signaling and neuro-inflammation, apoptosis and senescence
4) Perturbed coordination between DDR and DSB repair processes, leading to pathogenic mutations
5) The implications of defective DNA repair mechanisms in neurodegenerative diseases and aging