title: Centrosome-Dependent Bypass of the DNA Damage Checkpoint by the Polo Kinase Cdc5.
abstract: Cell-cycle checkpoints are essential feedback mechanisms that promote genome integrity. However, in the face of unrepairable DNA lesions, bypass mechanisms can suppress checkpoint activity and allow cells to resume proliferation. The molecular mechanisms underlying this biological response are currently not understood. Taking advantage of unique separation-of-function mutants, we show that the Polo-like kinase (PLK) Cdc5 uses a phosphopriming-based interaction mechanism to suppress G2/M checkpoint arrest by targeting Polo kinase activity to centrosomes. We also show that key subunits of the evolutionarily conserved RSC complex are critical downstream effectors of Cdc5 activity in checkpoint suppression. Importantly, the lethality and checkpoint defects associated with loss of Cdc5 Polo box activity can be fully rescued by artificially anchoring Cdc5 kinase domain to yeast centrosomes. Collectively, our results highlight a previously unappreciated role for centrosomes as key signaling centers for the suppression of cell-cycle arrest induced by persistent or unrepairable DNA damage.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada.
authors.forename: Hery
authors.initials: H
authors.lastname: Ratsima
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada.
authors.forename: Diego
authors.initials: D
authors.lastname: Serrano
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada.
authors.forename: Mirela
authors.initials: M
authors.lastname: Pascariu
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada. Electronic address: damien.damours@umontreal.ca.
authors.forename: Damien
authors.initials: D
authors.lastname: D'Amours
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015966:Gene Expression Regulation, Fungal; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C120195:4-nitroquinolone-1-oxide; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D015363:Quinolones; C103337:RSC complex, S cerevisiae; C107849:SAE2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D015112:4-Nitroquinoline-1-oxide; D008741:Methyl Methanesulfonate; D017346:Protein Serine-Threonine Kinases; C081927:CDC5 protein, S cerevisiae; D004720:Endonucleases