Question

Explain how the G1 Checkpoint in response to DNA damage works. Draw a diagram that indicates the proteins involved in this checkpoint and explain their roles in this process. Be sure to include all steps from the DNA damage to the arrest of the cell cycle.

Answer 1

The tumour suppressor gene p53 plays an important role in the arrest of cells with damaged DNA at the DNA damage checkpoint. p53 is responsible for cell cycle arrest at G1 and G2 phases . It is a transcription fact that regulates the expression of cell-cyle regulatory proteins. Under normal conditions it is highly unstable and is targeted for proteasomal degradation by a ubiquitin ligase named Mdm2

In case of DNA damage, the DNA-dependent protein kinase ATM (Ataxia Telangiectasia Mutate) and ATR are activated. ATM is a sensor of DNA damage caused by ionizing radiation and ATR recognises UV induced DNA damage. Both ATM and ATR inhibit DNA replication. When ATM or ATR detect DNA damage, they inhibit the rapid degradation of p53. ATM phosphorylates p53 at a site where Mdm2 binds to it. Mdm2 is unable to degrade p53. Due to this, the levels of p53 increase . Phosphorylated p53 acts as a transcription factor for the gene encoding p21, a CDK inhibitor protein (CKI). p21 binds with S-phase CDK and prevents them from binding cyclins thereby inhibiting them.