How does ATR regulate G2 arrest in the cell cycle?
How does ATR regulate G2 arrest in the cell cycle?
Answer
ATR (Ataxia Telangiectasia and Rad3-related protein) is a critical regulator of the G2/M checkpoint in the cell cycle, primarily functioning to maintain genomic integrity in response to DNA damage and replication stress. The activation of ATR is crucial for the induction of G2 arrest, allowing cells to repair DNA before entering mitosis.
Upon DNA damage or replication stress, ATR is activated and phosphorylates several downstream targets, including checkpoint kinases CHK1 and CHK2. This phosphorylation leads to the activation of these kinases, which play essential roles in mediating the G2/M checkpoint response (Negi & Brown, 2015; Zhao, 2024). Specifically, CHK1 phosphorylates CDC25C, a phosphatase that activates CDK1 (Cyclin-dependent kinase 1). The phosphorylation of CDC25C by CHK1 results in its degradation or inactivation, preventing the activation of CDK1 and thus inhibiting the transition from G2 to M phase (Hung et al., 2021; Chaudhary et al., 2013).
The role of ATR in G2 arrest is further underscored by its ability to maintain the inhibitory phosphorylation of CDC2 (also known as CDK1) at tyrosine 15 (CDC2(Y15)). This phosphorylation is crucial for preventing premature entry into mitosis, thereby allowing time for DNA repair mechanisms to act (Zhao, 2024; Hung et al., 2021; Chaudhary et al., 2013). In addition, ATR signaling can lead to the upregulation of p53, a tumor suppressor protein that also contributes to cell cycle arrest and DNA repair processes (Sharma & Bhonde, 2014; Luo et al., 2018).
Moreover, studies have shown that ATR not only responds to DNA damage but also plays a role in the regulation of the cell cycle under normal conditions. For instance, ATR is involved in the response to replication stress, which can occur even in the absence of overt DNA damage. This response is vital for preventing the accumulation of mutations and maintaining genomic stability (Negi & Brown, 2015; Warmerdam et al., 2013).
In summary, ATR regulates G2 arrest by activating checkpoint kinases that inhibit CDK1 activity, thereby preventing the cell from entering mitosis until DNA damage is repaired. This mechanism is essential for maintaining genomic integrity and preventing the propagation of damaged DNA during cell division.
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