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. 2019 Aug 8;13:778. doi: 10.3389/fnins.2019.00778

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Copyright © 2019 Li, Xie, Huang, Zhang, Zhou, Qi, Wang, Chen and Li.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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PIKKs-related signaling pathway in the aging brain. There are three types of phosphoinositide 3-kinase (PI3K)-related kinases (PIKKs) DNA-dependent protein kinase including ataxia-telangiectasia mutated (ATM), DNA protein kinase catalytic subunit (DNA-PKcs) and taxia-telangiectasia and Rad-3-related (ATR). ATM can be activated by double-strand breaks (DSB) and it phosphorylates a multitude of substrates, including nuclear respiratory factor 1 (NRF1), H2A histone family member X (H2AX), mediator of DNA damage checkpoint protein 1 (MDC1), p53-binding protein 1 (53BP1), breast cancer type 1 susceptibility protein (BRCA1) and MRE11/RAD50/NBS1 (MRN). As an interactor of ATM, ATMIN plays important role in its response to oxidative stress and aging related DNA damage. DNA-PKcs is required to form an active DNA-PK complex with Ku70/80. ATR is activated by single-strand breaks (SSB) and replication arrest. In aging and AD brain, all these DNA damage response pathways have been shown to progressively decline.