title: SCF(FBXW7α) modulates the intra-S-phase DNA-damage checkpoint by regulating Polo like kinase-1 stability.
abstract: The intra-S-checkpoint is essential to control cell progression through S phase under normal conditions and in response to replication stress. When DNA lesions are detected, replication fork progression is blocked allowing time for repair to avoid genomic instability and the risk of cancer. DNA replication initiates at many origins of replication in eukaryotic cells, where a series of proteins form pre-replicative complexes (pre-RCs) that are activated to become pre-initiation complexes and ensure a single round of replication in each cell cycle. PLK1 plays an important role in the regulation of DNA replication, contributing to the regulation of pre-RCs formation by phosphorylating several proteins, under both normal and stress conditions. Here we report that PLK1 is ubiquitinated and degraded by SCFFBXW7α/proteasome. Moreover, we identified a new Cdc4 phosphodegron in PLK1, conserved from yeast to humans, whose mutation prevents PLK1 destruction. We established that endogenous SCFFBXW7α degrades PLK1 in the G1 and S phases of an unperturbed cell cycle and in S phase following UV irradiation. Furthermore, we showed that FBXW7α overexpression or UV irradiation prevented the loading of proteins onto chromatin to form pre-RCs and, accordingly, reduced cell proliferation. We conclude that PLK1 degradation mediated by SCFFBXW7α modulates the intra-S-phase checkpoint.
authors: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla. Apartado de correos 1095. 41080-Sevilla, Spain.
authors: Servando
authors: S
authors: Giráldez
authors: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla. Apartado de correos 1095. 41080-Sevilla, Spain.
authors: Joaquín
authors: J
authors: Herrero-Ruiz
authors: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla. Apartado de correos 1095. 41080-Sevilla, Spain.
authors: Mar
authors: M
authors: Mora-Santos
authors: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Departamento de Anatomía Patológica, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain.
authors: Miguel Á
authors: MÁ
authors: Japón
authors: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla. Apartado de correos 1095. 41080-Sevilla, Spain.
authors: Maria
authors: M
authors: Tortolero
authors: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla. Apartado de correos 1095. 41080-Sevilla, Spain.
authors: Francisco
authors: F
authors: Romero
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D004249:DNA Damage; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D016196:S Phase; D053719:Tandem Mass Spectrometry; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C513272:Fbxw7 protein, mouse