title: Centrosomes in the DNA damage response--the hub outside the centre.
abstract: Here, we review how DNA damage affects the centrosome and how centrosomes communicate with the DNA damage response (DDR) apparatus. We discuss how several proteins of the DDR are found at centrosomes, including the ATM, ATR, CHK1 and CHK2 kinases, the BRCA1 ubiquitin ligase complex and several members of the poly(ADP-ribose) polymerase family. Stereotypical centrosome organisation, in which two centriole barrels are orthogonally arranged in a roughly toroidal pericentriolar material (PCM), is strongly affected by exposure to DNA-damaging agents. We describe the genetic dependencies and mechanisms for how the centrioles lose their close association, and the PCM both expands and distorts after DNA damage. Another consequence of genotoxic stress is that centrosomes undergo duplication outside the normal cell cycle stage, meaning that centrosome amplification is commonly seen after DNA damage. We discuss several potential mechanisms for how centrosome numbers become dysregulated after DNA damage and explore the links between the DDR and the PLK1- and separase-dependent mechanisms that drive centriole separation and reduplication. We also describe how centrosome components, such as centrin2, are directly involved in responding to DNA damage. This review outlines current questions on the involvement of centrosomes in the DDR.
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Biosciences Building, Dangan, Galway, Ireland.
authors.forename: Lisa I
authors.initials: LI
authors.lastname: Mullee
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Biosciences Building, Dangan, Galway, Ireland. Ciaran.Morrison@nuigalway.ie.
authors.forename: Ciaran G
authors.initials: CG
authors.lastname: Morrison
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C472752:CETN2 protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D009097:Multienzyme Complexes; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases
keywords: ATM; CHK1; Cancer; Centriole; Centrosome; Checkpoint; PCM; PLK1