title: The p97-Ufd1-Npl4 ATPase complex ensures robustness of the G2/M checkpoint by facilitating CDC25A degradation.
abstract: The p97-Ufd1-Npl4 ATPase complex is associated with the response to DNA damage and replication stress, but how its inactivation leads to manifestation of chromosome instability is unclear. Here, we show that p97-Ufd1-Npl4 has an additional direct role in the G2/M checkpoint. Upon DNA damage, p97-Ufd1-Npl4 binds CDC25A downstream of ubiquitination by the SCF-βTrCP ligase and facilitates its proteasomal degradation. Depletion of Ufd1-Npl4 leads to G2/M checkpoint failure due to persistent CDC25 activity and propagation of DNA damage into mitosis with deleterious effects on chromosome segregation. Thus, p97-Ufd1-Npl4 is an integral part of G2/M checkpoint signaling and thereby suppresses chromosome instability.
authors.affiliation: Centre for Medical Biotechnology; Faculty of Biology; University of Duisburg - Essen; Essen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Riemer
authors.affiliation: Centre for Medical Biotechnology; Faculty of Biology; University of Duisburg - Essen; Essen, Germany.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Dobrynin
authors.affiliation: Centre for Medical Biotechnology; Faculty of Biology; University of Duisburg - Essen; Essen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Dressler
authors.affiliation: Centre for Medical Biotechnology; Faculty of Biology; University of Duisburg - Essen; Essen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bremer
authors.affiliation: Institute of Medical Radiation Biology; University of Duisburg - Essen; Essen, Germany.
authors.forename: Aashish
authors.initials: A
authors.lastname: Soni
authors.affiliation: Institute of Medical Radiation Biology; University of Duisburg - Essen; Essen, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Iliakis
authors.affiliation: Centre for Medical Biotechnology; Faculty of Biology; University of Duisburg - Essen; Essen, Germany.
authors.forename: Hemmo
authors.initials: H
authors.lastname: Meyer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D020090:Chromosome Segregation; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D059566:M Phase Cell Cycle Checkpoints; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; C514112:NPLOC4 protein, human; D009687:Nuclear Proteins; D011506:Proteins; C491497:UFD1 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C404942:p97 ATPase
keywords: DNA damage; checkpoint; chromosome instability; degradation; ubiquitin