Figure 2
A model for inhibition of Cdt1 function after entry into S phase. Cyclin A/Cdks phosphorylate Cdt1 on threonine 29 depending on cyclin A binding to RXL-type cyclin-binding motif (Cy moif) then SCFSkp2 ubiquitin ligase recognizes phosphorylated Cdt1 and polyubiquitinated Cdt1 is degraded by proteasomes. In addition, Cdk phosphorylation inhibits Cdt1 DNA binding activity. During DNA replication, Cdt1 binds to PCNA on chromatin and Cul4-DDB1Cdt2 ubiquitin ligase recognizes interfaces generated by such Cdt1-PCNA interaction. This mechanism also appears to operate during repair synthesis of damaged DNA although the biological significance remains unclear. After S phase, geminin protein also accumulates, sequestering Cdt1 by direct binding.