When DNA damage occurs, or when the cell detects any defects which necessitate it to delay or halt the cell cycle in G1, arrest occurs through several mechanisms. The rapid response involves phosphorylation events that initiate with either kinase ATM (Ataxia telangiectasia mutated) or ATR (Ataxia Telangiectasia and Rad3 related), which act as sensors, depending on the type of damage. These kinases phosphorylate and activate the effector kinases Chk2 and Chk1, respectively, which in turn phosphorylate the phosphatase Cdc25A, thus marking it for ubiquitination and degradation. As Cdc25A activates the previously mentioned cyclin E-CDK2 complex by removing inhibitory phosphates from CDK2, in the absence of Cdc25A, cyclin E-CDK2 remains inactive, and the cell remains in G1. To maintain the arrest, another response is initiated, by which Chk2 or Chk1 phosphorylate p53, a tumor suppressor, and this stabilizes p53 by preventing it from binding Mdm2, a ubiquitin ligase which inhibits p53 by targeting it for degradation. The stable p53 then acts a transcriptional activator of several target genes, including p21, an inhibitor of the G1 - to - S promoting complex cyclin E-CDK21. In addition, another mechanism by which p21 is activated is through the accumulation of p16 in response to DNA damage. p16 disrupts cyclin D - CDK4 complexes, thus causing the release of p21 from the complexes, which leads to the dephosphorylation and activation of Rb, which allows Rb to bind and inhibit E2F1 - 3, thus keeping the cell from transitioning to S phase. Recently, some aspects of this model have been disputed.
which molecule initiates the halt of the cycle when damaged dna is detected in g1
Cdc25A Cdc25A Cdc25A