Degradation of Cdt1 during the cell cycle and after DNA damage. In S phase, Cdt1 degradation occurs by the SCF–Skp2 and by the PCNA–Cul4–Ddb1–Cdt2 pathways. Cyclin A/Cdk2 associates with Cdt1 on its Cy motif and phosphorylates Cdt1 at residue Thr-29, followed by recruitment of the SCF–Skp2 E3 ubiquitin ligase complex. PCNA binds to Cdt1 on its PIP motif, leading to recruitment of Cul4–Ddb1–Cdt2 E3 ubiquitin ligase complex. Cdt2 recognizes the degron motif (D) adjacent to the PIP box on Cdt1, which allows for binding of Cdt1 with Cdt2 thus promoting E3 ligase activity of the Cul4–Ddb1–Cdt2 complex. Following DNA damage by UV/IR irradiation, PCNA–Cul4–Ddb1–Cdt2 mediates Cdt1 degradation on chromatin in a similar manner as S-phase-induced degradation.