title: Heat shock protein 90α (Hsp90α) is phosphorylated in response to DNA damage and accumulates in repair foci.
abstract: DNA damage triggers a complex signaling cascade involving a multitude of phosphorylation events. We found that the threonine 7 (Thr-7) residue of heat shock protein 90α (Hsp90α) was phosphorylated immediately after DNA damage. The phosphorylated Hsp90α then accumulated at sites of DNA double strand breaks and formed repair foci with slow kinetics, matching the repair kinetics of complex DNA damage. The phosphorylation of Hsp90α was dependent on phosphatidylinositol 3-kinase-like kinases, including the DNA-dependent protein kinase (DNA-PK) in particular. DNA-PK plays an essential role in the repair of DNA double strand breaks by nonhomologous end-joining and in the signaling of DNA damage. It is also present in the cytoplasm of the cell and has been suggested to play a role in cytoplasmic signaling pathways. Using stabilized double-stranded DNA molecules to activate DNA-PK, we showed that an active DNA-PK complex could be assembled in the cytoplasm, resulting in phosphorylation of the cytoplasmic pool of Hsp90α. In vivo, reverse phase protein array data for tumors revealed that basal levels of Thr-7-phosphorylated Hsp90α were correlated with phosphorylated histone H2AX levels. The Thr-7 phosphorylation of the ubiquitously produced and secreted Hsp90α may therefore serve as a surrogate biomarker of DNA damage. These findings shed light on the interplay between central DNA repair enzymes and an essential molecular chaperone.
authors.affiliation: Institut Curie, CNRS UMR3347, INSERM U1021, Université Paris-Sud 11, Centre Universitaire, Orsay, France. maria.quanz@curie.fr
authors.forename: Maria
authors.initials: M
authors.lastname: Quanz
authors.forename: Aurélie
authors.initials: A
authors.lastname: Herbette
authors.forename: Mano
authors.initials: M
authors.lastname: Sayarath
authors.forename: Leanne
authors.initials: L
authors.lastname: de Koning
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Sun
authors.forename: Marie
authors.initials: M
authors.lastname: Dutreix
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051381:Rats
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human