DNA-PKcs strongly suppresses the exonuclease activity sellectchem of Artemis but allows limited endonucleolytic trimming, likely at regions of transition from single-strand to double-strand [39,42]. Figure 1 The DNA repair process by non-homologous end joining (NHEJ) and the role of DNA-dependent protein kinase (DNA-PK) subunits. Upon induction of double-strand break (DSB), DNA-PKcs and Ku80/Ku70 are rapidly recruited to DNA ends and DNA repair occurs in … Non-homologous end joining and DNA-dependent protein kinase in neurons Mature neurons are essentially post-mitotic and do not proliferate, whereas some glial cells can undergo replication especially as a response to stress or damage [43,44]. Neurons are also among the most metabolically and transcriptionally active cells (reviewed in [45]), thus making these cells vulnerable to risks that involve DNA damage.

DNA repair pathways in brain have been studied extensively over the last two decades (reviewed in [45,46]). In mammals, DSB repair uses two mechanisms: HR and NHEJ. NHEJ is the predominant dsDNA repair pathway in mammalian cells [47]. Compared with the HR, NHEJ is considered error-prone and imprecise as it acts at the DNA break sites to restore the chromosomal structural integrity which could come at the expense of one or a few nucleotides. Since most of the higher eukaryote genome is non-coding, error-prone rejoining of DSBs by NHEJ generally has minimal deleterious consequences. However, DSB repair in coding regions can potentially introduce functionally important coding changes.

Over time, as in aging, these small errors can accumulate, resulting in genome instability that leads to cellular dysfunction or death. Accordingly, it has been reported that 10% of p53 mutations in human cancers could be attributed to deletions arising from NHEJ sites [48]. NHEJ is also the predominant form of dsDNA repair pathway in post-mitotic neurons [49] and is critical in the nervous system development since mice deficient in DNA ligase IV, XRCC4, Ku70, and Ku 80, which are participants in the NHEJ event, show massive apoptosis Carfilzomib of post-mitotic neurons [46,50]. Loss of NHEJ activity in the developing brain can be prenatally lethal and, in adults, can lead to neurodegenerative diseases [46,51,52]. Mice with defective NHEJ show accelerated aging [53,54].

DNA-dependent protein kinase and cell-cycle re-entry in neurodegeneration leave a message One of the factors contributing to neurodegeneration is the re-entry of terminally differentiated post-mitotic neurons into the cell cycle because of chronic or acute insults associated with DNA damage and oxidative stress that result in apoptosis [55,56]. DSB repair capability is critical for neurogenesis during development, and damaged neurons demonstrate this by escaping apoptosis, re-entering the cell cycle, and incorporating into the developing brain, leading to neurodegeneration in mice with low or no ATM activity [57].