title: Mechanism of CRL4(Cdt2), a PCNA-dependent E3 ubiquitin ligase.
abstract: Eukaryotic cell cycle transitions are driven by E3 ubiquitin ligases that catalyze the ubiquitylation and destruction of specific protein targets. For example, the anaphase-promoting complex/cyclosome (APC/C) promotes the exit from mitosis via destruction of securin and mitotic cyclins, whereas CRL1(Skp2) allows entry into S phase by targeting the destruction of the cyclin-dependent kinase (CDK) inhibitor p27. Recently, an E3 ubiquitin ligase called CRL4(Cdt2) has been characterized, which couples proteolysis to DNA synthesis via an unusual mechanism that involves display of substrate degrons on the DNA polymerase processivity factor PCNA. Through its destruction of Cdt1, p21, and Set8, CRL4(Cdt2) has emerged as a master regulator that prevents rereplication in S phase. In addition, it also targets other factors such as E2F and DNA polymerase η. In this review, we discuss our current understanding of the molecular mechanism of substrate recognition by CRL4(Cdt2) and how this E3 ligase helps to maintain genome integrity.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Havens
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Walter
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology; D004261:DNA Replication / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D029867:Xenopus Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C429530:DTL protein, human; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D029867:Xenopus Proteins; C552111:dtl protein, Xenopus; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases