title: CDK1-dependent inhibition of the E3 ubiquitin ligase CRL4CDT2 ensures robust transition from S Phase to Mitosis.
abstract: Replication-coupled destruction of a cohort of cell cycle proteins ensures efficient and precise genome duplication. Three proteins destroyed during replication via the CRL4(CDT2) ubiquitin E3 ligase, CDT1, p21, and SET8 (PR-SET7), are also essential or important during mitosis, making their reaccumulation after S phase a critical cell cycle event. During early and mid-S phase and during DNA repair, proliferating cell nuclear antigen (PCNA) loading onto DNA (PCNA(DNA)) triggers the interaction between CRL4(CDT2) and its substrates, resulting in their degradation. We have discovered that, beginning in late S phase, PCNA(DNA) is no longer sufficient to trigger CRL4(CDT2)-mediated degradation. A CDK1-dependent mechanism that blocks CRL4(CDT2) activity by interfering with CDT2 recruitment to chromatin actively protects CRL4(CDT2) substrates. We postulate that deliberate override of replication-coupled destruction allows anticipatory accumulation in late S phase. We further show that (as for CDT1) de novo SET8 reaccumulation is important for normal mitotic progression. In this manner, CDK1-dependent CRL4(CDT2) inactivation contributes to efficient transition from S phase to mitosis.
authors.affiliation: From the Curriculum in Genetics and Molecular Biology and.
authors.forename: Lindsay F
authors.initials: LF
authors.lastname: Rizzardi
authors.affiliation: From the Curriculum in Genetics and Molecular Biology and.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Coleman
authors.affiliation: the Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Dileep
authors.initials: D
authors.lastname: Varma
authors.affiliation: the Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Matson
authors.affiliation: the Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Seeun
authors.initials: S
authors.lastname: Oh
authors.affiliation: From the Curriculum in Genetics and Molecular Biology and the Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599 jgcook@email.unc.edu.
authors.forename: Jeanette Gowen
authors.initials: JG
authors.lastname: Cook
mesh_terms: D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008938:Mitosis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D016196:S Phase; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; C429530:DTL protein, human; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D044767:Ubiquitin-Protein Ligases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases
keywords: CDT1; CDT2; Cell Cycle; Cyclin-dependent Kinase (CDK); DNA Replication; E3 Ubiquitin Ligase; Mitosis; PCNA; SET8; p21