Serine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1) is an enzyme that, in humans, is encoded by the ATR gene. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. It is a serine/threonine-specific protein kinase that is involved in sensing DNA damage and activating the DNA damage checkpoint, leading to cell cycle arrest. ATR is activated in response to persistent single-stranded DNA, which is a common intermediate formed during DNA damage detection and repair. Single-stranded DNA occurs at stalled replication forks and as an intermediate in DNA repair pathways such as nucleotide excision repair and homologous recombination repair. ATR works with a partner protein called ATRIP to recognize single-stranded DNA coated with RPA.
An Overview of ATR
Ataxia telangiectasia mutant gene Rad3 associated kinase (ATR) is an important regulatory factor for the mechanism of DNA damage repair (DDR). ATR is a member of phosphatidylinositol 3-kinase associated kinase protein family. It consists of 2644 amino acids, and its N-terminal is ATR interaction protein (ATR-interacting-protein, ATRIP) binding domain, which is an important domain activated by ATR. It has been found that ATR molecular pathways regulate DNA damage and repair through a variety of cytokines, leading to the development of normal cells into tumor cells. Some of these inhibitors have shown significant anti-tumor effects and have entered clinical trials.
Inhibition of ATR
At present, many ATR inhibitors have been reported, such as VX-970 and AZD6738. According to the structural characteristics of the existing ATR inhibitors, the inhibitors can be classified into pyrimidines, pyrazines and pyridines. In addition to the representative compounds mentioned above, it was found that other inhibitors including caffeine, schisandrin B, wortmannin and so on, had inhibitory effects on ATR. Caffeine can interfere with the cell cycle arrest and breakdown induced by DNA damage. The mechanism of DNA damage response promotes tumor cell death.
ATR and diseases
As a mechanism of DNA damage response, ATR pathway plays an important role in tumor survival. The inhibition of ATR, a key factor, can induce the death of ATR pathway dependent malignant tumor cells and have little effect on the reproduction and growth of normal cells. It is an ideal target for the development of low toxicity and high efficiency targeted antitumor drugs. The results showed that ATR was mainly blocked by cell cycle progression. Stable replication forks and promoting DNA repair to promote cell survival. ATR inhibitors alone or in conjunction with other antitumor drugs have a strong inhibitory effect on ATR dependent tumor cells. Therefore, selective inhibition of ATR provides a new approach to limping treatment and a new tool for tumor research.