title: Link between DNA damage and centriole disengagement/reduplication in untransformed human cells.
abstract: The radiation and radiomimetic drugs used to treat human tumors damage DNA in both cancer cells and normal proliferating cells. Centrosome amplification after DNA damage is well established for transformed cell types but is sparsely reported and not fully understood in untransformed cells. We characterize centriole behavior after DNA damage in synchronized untransformed human cells. One hour treatment of S phase cells with the radiomimetic drug, Doxorubicin, prolongs G2 by at least 72 h, though 14% of the cells eventually go through mitosis in that time. By 72 h after DNA damage we observe a 52% incidence of centriole disengagement plus a 10% incidence of extra centrioles. We find that either APC/C or Plk activities can disengage centrioles after DNA damage, though they normally work in concert. All disengaged centrioles are associated with γ-tubulin and maturation markers and thus, should in principle be capable of reduplicating and organizing spindle poles. The low incidence of reduplication of disengaged centrioles during G2 is due to the p53-dependent expression of p21 and the consequent loss of Cdk2 activity. We find that 26% of the cells going through mitosis after DNA damage contain disengaged or extra centrioles. This could produce genomic instability through transient or persistent spindle multipolarity. Thus, for cancer patients the use of DNA damaging therapies raises the chances of genomic instability and evolution of transformed characteristics in proliferating normal cell populations.
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Stephen
authors: S
authors: Douthwright
authors: Greenfield
authors: G
authors: Sluder
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000037:antagonists & inhibitors / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002502:Centrioles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000633:toxicity*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D042822:Genomic Instability; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D064173:Anaphase-Promoting Complex-Cyclosome; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004317:Doxorubicin; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C493956:CDKN1A protein, human; C495901:TP53 protein, human; C495894:CDK2 protein, human