<P> The G1 checkpoint, also known as the restriction point in mammalian cells and the start point in yeast, is the point at which the cell becomes committed to entering the cell cycle . As the cell progresses through G1, depending on internal and external conditions, it can either delay G1, enter a quiescent state known as G0, or proceed past the restriction point . The decision to commit to a new round of cell division occurs when the cell activates cyclin - CDK - dependent transcription which promotes entry into S phase . </P> <P> During early G1, the transcriptional repressors Rb (retinoblastoma), p107 and p130, known as pocket proteins, bind to the E2F transcription factors to prevent G1 - to - S transition . Rb binds and represses activator E2F transcription factors (E2F1 - 3), while p107 and p130 bind E2F4 and E2F5 respectively to form complexes which repress transcription of G1 - to - S promoting factors (proteins). Upon the decision to progress past the G1 checkpoint, cyclin D levels rise, and cyclin D forms a complex with CDK4 and CDK6, which in turn phosphorylate the pocket proteins . Phosphorylation of the pocket proteins causes the release of their bound targets, thereby relieving the repression of the E2F1 - 3 activators and translocating repressors E2F4 and E2F5 from the nucleus to the cytoplasm . This results in the transcriptional activation of downstream targets, which promote the G1 - to - S transition, including another cyclin, known as cyclin E, which forms a complex with CDK2 . The formation of the cyclin E-CDK2 complex then promotes a positive feedback loop which creates an "all or nothing" switch from which the cell cannot return . Following entry to S - phase and initiation of DNA replication, S - phase cyclin A, a transcriptional target of E2F1 - 3, forms a complex with CDK2 which phosphorylates E2F1 - 3 and prevents its ability to bind to DNA, thus forming a negative feedback loop . In another negative feedback loop, E2F1 - 3 promote the transcription of E2F6 - 8, which in turn repress G1 - S transition . </P> <P> 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 . </P> <P> Following DNA replication in S phase, the cell undergoes a growth phase known as G2 . During this time, necessary mitotic proteins are produced and the cell is once more subjected to regulatory mechanisms to ensure proper status for entry into the proliferative Mitotic (M) phase . Multiple mechanistic checkpoints are involved in this transition from G2 to M, with a common uniting factor of cyclin - Cdk activity . </P>

Which molecule initiates the halt of the cycle when damaged dna is detected in g1