title: The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression.
abstract: DNA polymerase δ (Pol δ) is a key enzyme in eukaryotic DNA replication. Human Pol δ is a heterotetramer whose p12 subunit is degraded in response to DNA damage, leading to the in vivo conversion of Pol δ4 to Pol δ3. 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 δ3 and ubiquitinated PCNA for DNA repair processes. CRL4(Cdt2) partially degrades p12 during normal cell cycle progression, thereby generating Pol δ3 during S phase. This novel finding extends the current view of the role of Pol δ3 in DNA repair and leads to the hypothesis that it participates in DNA replication. The coordinated regulation of licensing factors and Pol δ3 by CRL4(Cdt2) now opens new avenues for control of DNA replication. A parallel study of Pol δ4 and Pol δ3 in Okazaki fragment processing provides evidence for a role of Pol δ3 in DNA replication. We discuss several new perspectives of the role of the 2 forms of Pol δ in DNA replication and repair, as well the significance of the integration of p12 regulation in DNA repair and cell cycle progression.
authors.affiliation: Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla, NY USA.
authors.forename: Marietta Y W T
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla, NY USA.
authors.forename: Sufang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla, NY USA.
authors.forename: Szu Hua Sharon
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla, NY USA.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology; Brander Cancer Research Institute; New York Medical College; Valhalla, NY USA.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Darzynkiewicz
authors.affiliation: Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla, NY USA.
authors.forename: Zhongtao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology; New York Medical College; Valhalla, NY USA.
authors.forename: Ernest Y C
authors.initials: EY
authors.lastname: Lee
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C022262:Okazaki fragments; D021122:Protein Subunits; D025801:Ubiquitin; D004247:DNA; D044767:Ubiquitin-Protein Ligases; C521101:POLD4 protein, human; D004258:DNA Polymerase III
keywords: CRL4Cdt2; DNA damage; DNA polymerase δ; DNA replication; RNF8; cell cycle; cell cycle progression; p12 subunit