title: Inhibition of Polo-like kinase 1 during the DNA damage response is mediated through loss of Aurora A recruitment by Bora.
abstract: When cells in G2 phase are challenged with DNA damage, several key mitotic regulators such as Cdk1/Cyclin B, Aurora A and Plk1 are inhibited to prevent entry into mitosis. Here we have studied how inhibition of Plk1 is established after DNA damage. Using a Förster resonance energy transfer (FRET)-based biosensor for Plk1 activity, we show that inhibition of Plk1 after DNA damage occurs with relatively slow kinetics and is entirely dependent on loss of Plk1-T210 phosphorylation. As T210 is phosphorylated by the kinase Aurora A in conjunction with its co-factor Bora, we investigated how they are affected by DNA damage. Interestingly, we find that the interaction between Bora and Plk1 remains intact during the early phases of the DNA damage response (DDR), whereas Plk1 activity is already inhibited at this stage. Expression of an Aurora A mutant that is refractory to inhibition by the DDR failed to prevent inhibition of Plk1 and loss of T210 phosphorylation, suggesting that inhibition of Plk1 may be established by perturbing recruitment of Aurora A by Bora. Indeed, expression of a fusion in which Aurora A was directly coupled to Bora prevented DNA damage-induced inhibition of Plk1 activity, as well as inhibition of T210 phosphorylation. Taken together, these data demonstrate that DNA damage affects the function of Aurora A at multiple levels: both by direct inhibition of Aurora A activity, as well as by perturbing the interaction with its co-activator Bora. We propose that the DDR targets recruitment of Aurora A to the Plk1/Bora complex to prevent activation of Plk1 during DNA damage in G2.
authors.affiliation: Department of Cell Biology and Cancer Genomics Center (CGC.nl), The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: W
authors.identifier: 0000-0001-7616-2979
authors.initials: W
authors.lastname: Bruinsma
authors.affiliation: Department of Cell Biology and Cancer Genomics Center (CGC.nl), The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Aprelia
authors.affiliation: Department of Cell Biology and Cancer Genomics Center (CGC.nl), The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: I
authors.initials: I
authors.lastname: García-Santisteban
authors.affiliation: Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kool
authors.affiliation: Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Department of Cell Biology and Cancer Genomics Center (CGC.nl), The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D000097869:Polo-Like Kinase 1
chemical_list: D064096:Aurora Kinase A; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C528235:bora protein, human