1.) which Cdk and cyclin comes under G1 check point.
2.) which Cdk and cyclin comes under G2 check point.
Answers
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i) 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.[1] DNA damage is the main indication for a cell to "restrict"and not enter the cell cycle. 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
ii) 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.
Although variations in requisite cyclin-Cdk complexes exist across organisms, the necessity of the kinase activity is conserved and typically focuses on a single pairing. In fission yeast three different forms of mitotic cyclin exist, and six in budding yeast, yet the primary cyclin utilized is cyclin B.[11] Cyclin B will serve as reference for discussion of the G2/M checkpoint transition.
Similar to S Phase, G2 experiences a DNA damage checkpoint. The cell is once more examined for sites of DNA damage or incomplete replication, and the kinases ATR and ATM recruited to damage sites. Activation of Chk1 and Chk2 also transpire, as well as p53 activation, to induce cell cycle arrest and halt progression into mitosis. An additional component of S phase, the Pre-Replicative Complex, must be inactivated via cyclin B-Cdk1 phosphorylation.[12]
As these previous checkpoints are assessed, G2 protein accumulation serves to activate cyclinB-Cdk1 activity via multiple mechanisms. CyclinA-Cdk2 activates Cdc25, an activator of cyclinB-Cdk1, which then deactivates the cyclinB-Cdk1 inhibitor, Wee1. This results in a positive feedback loop, significantly increasing cyclinB expression and Cdk1 activation. As the cell progresses through G2 and reaches the G2/M transition, the kinase Plk1 phosphorylates Wee1, which targets Wee1 for degradation via the SCF ubiquitin ligase complex.[13] An additional function of Plk1 is to activate Cdc25 through phosphorylation. The compound effect of Wee1 degradation and Cdc25 activation is the net removal of inhibitory phosphorylation from cdc2, which activates cdc2. Plk1 is activated at the G2/M transition by the Aurora A and Bora, which accumulate during G2 and form an activation complex. The Plk1-Cdc2-cdc25 complex then initiates a positive feedback loop which serves to further activate Cdc2, and in conjunction with an increase in cyclin B levels during G2, the resulting cdc2-cyclin B complexes then activate downstream targets which promote entry into mitosis.[14]The resultant Cdk1 activity also activates expression of Mem1-Fkh, a G2/M transition gene.[15] The rapid surge in cyclinB-Cdk1 activity is necessary, as M phase initiation is an all-or-nothing event engaging in hysteresis. Hysteresis of Cdk1 activity via cyclin B drives M phase entry by establishing a minimum threshold of cyclinB concentration. This exists at a level higher than the minimum needed for the continuation of M phase after entry, acting to safeguard the all-or-nothing event. This entry concentration is further increased in the case of incomplete DNA replication, adding another regulatory mechanism at the G2/M transition point.[16] The presence of hysteresis allows for M phase entry to be highly regulated as a function of cyclinB-Cdk1 activity.
The mechanisms by which mitotic entry is prevented in response to DNA damage are similar to those in the G1/S checkpoint. DNA damage triggers the activation of the aforementioned ATM/ATR pathway, in which ATM/ATR phosphorylate and activate the Chk1/Chk2 checkpoint kinases. Chk1/2 phosphorylate cdc25 which, in addition to being inhibited, is also sequestered in the cytoplasm by the 14-3-3 proteins. 14-3-3 are upregulated by p53, which, as previously mentioned, is activated by Chk1 and ATM/ATR. p53 also transactivates p21, and both p21 and the 14-3-3 in turn inhibit cyclin B-cdc2 complexes through the phosphorylation and cytoplasmic sequestering of cdc2. In addition, the inactivation of cdc25 results in its inability to dephosphorylate and activate cdc2.[17][18]Finally, another mechanism of damage response is through the negative regulation of Plk1 by ATM/ATR, which in turn results in the stabilization of Wee1 and Myt1, which can then phosphorylate and inhibit cdc2, thus keeping the cell arrested in G2 until the damage is fixed.[19]
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