ATR structure and function
ATR is a 300 kDa protein, which is divided into ATRIP-interacting domain, kinase domain and other domains according to its function. The N-terminal ATRIP binding domain is an important domain for ATR activation, and the C-terminal kinase domain is an important domain for ATR phosphorylation downstream proteins. ATR is a member of the phosphatidylinositol 3-kinase related kinase (PIKK) protein family and has the function of phosphorylating serine or threonine of the target protein. It plays an important role in cell growth metabolism, DNA damage repair and other processes. The sequence of its kinase domain is very similar to the proteins of the phosphatidylinositol 3-kinase (PI3K) family. ATR is involved in a wider range of DNA damage repair types than ATM, and plays a key role in stabilizing DNA during replication. ATR can sense the damage caused by ultraviolet rays and phosphorylate downstream proteins such as p53, Chk1, claspin, etc., thereby regulating nucleotide excision repair, cell cycle and cell apoptosis.
ATR Regulates UV-Induced Apoptosis
Apoptosis (apoptosis) is an important regulation method to maintain the microenvironment of the organism. When the cell is damaged and cannot be repaired, the apoptosis process is initiated, and the damaged cell will be apoptotic to protect the individual. The pathway of UV-induced apoptosis can be divided into p53-independent apoptosis and p53-dependent apoptosis. There are three ways of p53-independent apoptosis: UV radiation induces the release or increase of death ligand on the cell membrane, and increases the binding with death receptor to activate apoptosis; UV radiation directly causes the cell membrane to Aggregation of death receptors does not require the presence of death ligands to activate apoptosis; ultraviolet radiation causes the release of cytochrome C in the mitochondria, activating the apoptotic pathway. UV-induced apoptosis is mainly regulated by the p53-dependent pathway, which is regulated by ATR: after UV damage, ATR is activated, p53 is phosphorylated, p53 and MDM2 are dissociated, and p53 is degraded by ubiquitination. When DNA damage cannot be repaired, phosphorylated p53 can activate Apaf1, Apaf1 cleaves caspase9, and then caspase9 cleaves caspase3 to activate. Caspase3 acts as an effector protein for apoptosis, and p53 can also inhibit mitochondria. Cytochrome C activated apoptotic pathway. However, scientist found in human keratinocytes that ATR regulates apoptosis caused by ultraviolet rays through phosphorylation of Chk1, and p53 is not involved. This indicates that ATR may phosphorylate Chk1 or p53 to regulate cell apoptosis, but the specific process of ATR regulating cell apoptosis through Chk1 has not been elucidated, and further research is needed.
Functions
ATR is a serine/threonine-specific protein kinase that is involved in sensing DNA damage and activating DNA damage checkpoints, resulting in cell cycle arrest. ATR is activated in response to persistent single-stranded DNA, a common intermediate formed during the detection and repair of DNA damage. Single-stranded DNA occurs at stalled replication forks and acts as an intermediate in DNA repair pathways such as nucleotide excision repair and homologous recombination repair. ATR, together with a chaperone protein called ATRIP, recognizes single-stranded DNA wrapped in RPA. Once ATR is activated, it phosphorylates Chk1, thereby initiating a signal transduction cascade, which eventually leads to cell cycle arrest. In addition to its function to activate DNA damage checkpoints, ATR is also thought to play a role in interference-free DNA replication. ATR is related to a second checkpoint-activated kinase, ATM, which is destroyed by double-strand breaks or chromatin disruption of DNA activation.
Clinical significance
ATR mutation is the cause of Seckel syndrome, a rare human disease that has certain characteristics with ataxia capillary dilatation caused by ATM mutations. ATR is also associated with familial skin capillary dilatation and cancer syndrome. ATR/ChK1 inhibitors can enhance the effect of DNA cross-linking agents. AstraZeneca has initiated the first clinical trial using ATR inhibitors, preferably in patients with ATM-mutated chronic lymphocytic leukemia (CLL), prelymphocytic leukemia (PLL) or B-cell lymphoma, and has been performed by Vertex Pharmaceuticals treats advanced solid tumors.
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