Atr, also known as ataxia-telangiectasia-mutated-and-Rad3-related kinase, is a key regulator in the DNA damage response (DDR) network. It coordinates processes like the replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair [4]. Atr is activated by replication stress and plays a crucial role in preventing cells with damaged or incompletely replicated DNA from entering mitosis, especially important in cancer cells with a defective G1 checkpoint due to p53 mutations [1].

In Atr-deficient cells, stalled replication forks undergo nucleus-wide breakage after unscheduled origin firing exhausts the nuclear pool of RPA, leading to "replication catastrophe" [2]. This shows that Atr-mediated suppression of dormant origins shields active forks against irreversible breakage by preventing RPA exhaustion. In intervertebral disc degeneration (IVDD), Atr deficiency destroys genomic integrity, causing cytosolic mislocalization of genomic DNA, which activates the cGAS/STING axis and promotes NP cell inflammatory senescence [3].

In conclusion, Atr is essential for maintaining genomic integrity during DNA replication and repair. Model-based research, especially Atr-deficient models, has revealed its role in cancer and IVDD. In cancer, its inhibition shows potential as a therapeutic strategy, while in IVDD, it provides a target to mitigate the disease progression.

References:

1. Qiu, Zhaojun, Oleinick, Nancy L, Zhang, Junran. 2017. ATR/CHK1 inhibitors and cancer therapy. In Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 126, 450-464. doi:10.1016/j.radonc.2017.09.043. https://pubmed.ncbi.nlm.nih.gov/29054375/

2. Toledo, Luis Ignacio, Altmeyer, Matthias, Rask, Maj-Britt, Bartek, Jiri, Lukas, Jiri. . ATR prohibits replication catastrophe by preventing global exhaustion of RPA. In Cell, 155, 1088-103. doi:10.1016/j.cell.2013.10.043. https://pubmed.ncbi.nlm.nih.gov/24267891/

3. Zhang, Weifeng, Li, Gaocai, Zhou, Xingyu, Zhao, Kangcheng, Yang, Cao. 2024. Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration. In The Journal of clinical investigation, 134, . doi:10.1172/JCI165140. https://pubmed.ncbi.nlm.nih.gov/38488012/

4. Mavroeidi, Dimitra, Georganta, Anastasia, Panagiotou, Emmanouil, Syrigos, Konstantinos, Souliotis, Vassilis L. 2024. Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes. In International journal of molecular sciences, 25, . doi:10.3390/ijms25052767. https://pubmed.ncbi.nlm.nih.gov/38474014/