Practice question

G1 progression toward S phase is driven by cyclin-dependent kinases CDK4/6-cyclin D and CDK2-cyclin E that phosphorylate retinoblastoma protein Rb, releasing transcription factor E2F to induce genes for DNA replication enzymes, nucleotide biosynthesis, and replication licensing factors such as Cdc6. DNA damage in G1 would risk copying lesions, necessitating arrest. Tumor suppressor p53 serves as guardian by acting as transcription factor stabilized upon ATM-CHK2 signaling after double-strand breaks. One of its principal targets is CDKN1A encoding p21CIP1/WAF1, a potent inhibitor of CDK2-cyclin E and CDK2-cyclin A complexes. p21 binds and inhibits kinase active site, preventing phosphorylation of Rb and downstream substrates like Cdc6 and keeping E2F repressed, thereby imposing G1 arrest and allowing time for repair. p53 also induces GADD45 and 14-3-3 sigma contributing to pause. p53 does not degrade Rb, directly phosphorylate Cdc25, or ubiquitinate securin; those actions belong to other regulators. Through p21 induction, p53 enforces G1 checkpoint, and loss of this axis contributes to unchecked proliferation and genomic instability in majority of human cancers.