title: Loss of CCDC6 affects cell cycle through impaired intra-S-phase checkpoint control.
abstract: In most cancers harboring Ccdc6 gene rearrangements, like papillary thyroid tumors or myeloproliferative disorders, the product of the normal allele is supposed to be functionally impaired or absent. To address the consequence of the loss of CCDC6 expression, we applied lentiviral shRNA in several cell lines. Loss of CCDC6 resulted in increased cell death with clear shortening of the S phase transition of the cell cycle. Upon exposure to etoposide, the cells lacking CCDC6 did not achieve S-phase accumulation. In the absence of CCDC6 and in the presence of genotoxic stress, like etoposide treatment or UV irradiation, increased accumulation of DNA damage was observed, as indicated by a significant increase of pH2Ax Ser139. 14-3-3σ, a major cell cycle regulator, was down-regulated in CCDC6 lacking cells, regardless of genotoxic stress. Interestingly, in the absence of CCDC6, the well-known genotoxic stress-induced cytoplasmic sequestration of the S-phase checkpoint CDC25C phosphatase did not occur. These observations suggest that CCDC6 plays a key role in cell cycle control, maintenance of genomic stability and cell survival and provide a rational of how disruption of CCDC6 normal function contributes to malignancy.
authors.affiliation: Department of Genetics & Gene Therapy, Biomedical Research Foundation of Academy of Athens, Athens, Greece.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Thanasopoulou
authors.forename: Dimitrios J
authors.initials: DJ
authors.lastname: Stravopodis
authors.forename: Konstantinos S
authors.initials: KS
authors.lastname: Dimas
authors.forename: Juerg
authors.initials: J
authors.lastname: Schwaller
authors.forename: Ema
authors.initials: E
authors.lastname: Anastasiadou
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000378:metabolism*; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D005092:Exonucleases / Q000378:metabolism; D005095:Exoribonucleases; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; D005047:Etoposide; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases