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BRAT1 (BRCA1-associated ATM activator 1) is involved in DNA damage response. It plays an important role in regulating mitochondrial function and cell proliferation.
In the course of injury, cells are susceptible to various stress conditions, including DNA damage that leads to double strand breaks. Without repair, these breaks can lead to distortion in DNA replication and transcription, leading to apoptosis. A major response to DNA damage is provided by the protein kinase ATM (ataxia telangiectasia mutated) that is capable of commanding a lot of signaling networks for DNA repair, cell cycle arrest, and even apoptosis. ATM is a member of the phosphatidylinositol 3 kinase-like kinase (PIKK) family of Ser/Thr-protein kinases, which includes ATR (ataxia-telangiectasia and Rad3-related), DNA-PKcs (DNA-dependent protein kinase catalytic subunit) and mTOR (mammalian target of rapamycin), among others. A key element in the DNA damage response is the redeployment of activating proteins into the cell nucleus to repair damaged DNA. BRAT1 is one of these proteins, and it functions as an activator of ATM by maintaining its phosphorylated status while also keeping other phosphatases at bay. Following double-strand DNA breaks and oxidation, ATM is recruited and activated by cell sensor proteins, including the MRE11-RAD50-NBS1 complex. ATM mobilization and activation at sites of broken DNA requires the participation of multiple sensor proteins. Aside from the MRE11-RAD50-NBS1 complex, a number of other sensor proteins have been identified including TP53BP1 (p53-binding protein 1), BRCA1 (breast cancer type 1), MDC1 (mediator of DNA damage checkpoint protein 1) and BRAT1. BRAT1 has been identified to be important for ATM phosphorylation at Ser1981 and complex assembly. Previous reports had shown that Ndfip1 is a cytoplasmic protein, whereas BRAT1 can shuttle between the cytoplasmand nucleus.
Fig. 1 Schematic model of BRAT1 function in regulating ATM/DNA-PKcs phosphorylation.
So et al. has shown that loss of BRAT1 expression significantly decreases cell proliferation and tumorigenecity both in vitro and in vivo. Cell migration also decreased significantly when BRAT1 was depleted. Interestingly, glucose uptake and production of mitochondrial ROS (reactive oxygen species) are highly increased in BRAT1 knockdown HeLa cells. Furthermore, in these cells, Akt and Erk bases and induced kinase activities are inhibited, suggesting abnormal signaling cascade of cell growth. Consequently, treating BRAT1 knockout cells with Akt activator improves their proliferation and reduces mitochondrial ROS concentration.
There is also some data suggested a potential role of BRAT1 in protein stability and regulation of mTOR signaling. BRAT1 can mTOR bound to and Raptor, but Akt is not present in the BRAT1 complex. This result suggests that BRAT1 can bind to proteins of TOCR1, rather than upstream or TOCR2 complex. BRAT1 functions in cell growth through PI3K/Akt/mTOR cascades. It has been reported that mTOR controls mitochondrial oxidative function through an YY1-PGC-1 transcriptional complex. And ATM plays roles in cell growth control, lymphoid differentiation, and neural stem cell differentiation. Therefore, further extended study about BRAT1 roles in PIKK-mediated signaling and relevance in cell growth and mitochondrial functions will give us not only basic understanding for collaboration between BRAT1 and PIKKs, but also one of solutions to develop therapeutic target for cancer treatment.
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