The tail that wags the dog p12, the smallest subunit of DNA polymerase delta, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

DNA polymerase delta (Pol delta) is a key enzyme in eukaryotic DNA replication. Human Pol delta is a heterotetramer whose p12 subunit is degraded in response to DNA damage, leading to the in vivo conversion of Pol delta 4 to Pol delta 3. Two E3 ubiquitin ligases, RNF8 and CRL4(Cdt2), participate in the DNA damage-induced degradation of p12. We discuss how these E3 ligases integrate the formation of Pol delta 3 and ubiquitinated PCNA for DNA repair processes. CRL4(Cdt2) partially degrades p12 during normal cell cycle progression, thereby generating Pol delta 3 during S phase. This novel finding extends the current view of the role of Pol delta 3 in DNA repair and leads to the hypothesis that it participates in DNA replication. The coordinated regulation of licensing factors and Pol delta 3 by CRL4(Cdt2) now opens new avenues for control of DNA replication. A parallel study of Pol delta 4 and Pol delta 3 in Okazaki fragment processing provides evidence for a role of Pol delta 3 in DNA replication. We discuss several new perspectives of the role of the 2 forms of Pol delta in DNA replication and repair, as well the significance of the integration of p12 regulation in DNA repair and cell cycle progression.