Neuronal DNA damage is linked to the re-entry of neurons into the cell cycle [56,58]. When post-mitotic neurons try to re-enter the cell cycle, www.selleckchem.com/products/chir-99021-ct99021-hcl.html the very attempt to transcribe a subset of cell cycle-related genes that have not been transcribed for years in the lifetime of a mature neuron may accumulate damaged DNA, which could trigger neuronal apoptosis [59]. Furthermore, it has been suggested that DNA replication resulted when cell-cycle re-entry preceded neurodegeneration in AD brains [60]. Reactive oxygen/nitrogen species are reported to cause unscheduled and incomplete DNA replication known as ‘replication stress’ [61]. Thus, inefficient DNA replication posing ‘replication stress’ in AD pathogenesis leading to genomic instability potentially links A?? accumulation and erroneous cell-cycle pathways [62].

Obviously, incomplete DNA replication due to DSBs or defective DNA repair systems (or both) would be highly probable in post-mitotic neurons, causing replication stress and subsequently leading to accelerated accumulation of further DNA damages and genomic instabilities [63,64]. Stalled replication forks collapse to yield one-ended DSBs, or ‘double-strand ends’, and abnormal DNA replication in post-mitotic neurons may be the source of intracellular increase in DNA content observed in AD brains [60,65]. AV-951 It has been shown that DNA-PKcs mutant cells fail to arrest replication following stress [66]. Additionally, studies show that, in response to replication stress-induced DNA damage, DNA-PK phosphorylates replication protein A (RPA) and dissociates RPA:DNA-PK complex [67,68], thereby inhibiting HR [69].

Thus, reduced DNA-PK activity in a cell could potentially induce replication stress and genome instability. DNA-dependent protein kinase in Alzheimer’s disease and add to your list aging It has also been shown that cells from old mice contain more DSBs than cells from young mice and that the fidelity and efficiency decline significantly during cellular senescence [70]. This event may contribute to age-related genomic instability and aging. DNA-PK plays critical roles in, first, detecting DNA damage and, then, triggering signaling pathways, including programmed cell death [53]. Ku80?/? mice are defective in the NHEJ and telomere maintenance and show premature aging, but surprisingly no human disorder caused by Ku80 deficiency or mutation has been reported [54,71].Interestingly, Ku80 and DNA-PKcs protein levels as well as the DNA-binding ability of Ku80 are reduced following severe ischemic injury, which causes extensive neuronal death in rabbits [72].