title: Coordination of centrosome homeostasis and DNA repair is intact in MCF-7 and disrupted in MDA-MB 231 breast cancer cells.
abstract: When cells encounter substantial DNA damage, critical cell cycle events are halted while DNA repair mechanisms are activated to restore genome integrity. Genomic integrity also depends on proper assembly and function of the bipolar mitotic spindle, which is required for equal chromosome segregation. Failure to execute either of these processes leads to genomic instability, aging, and cancer. Here, we show that following DNA damage in the breast cancer cell line MCF-7, the centrosome protein centrin2 moves from the cytoplasm and accumulates in the nucleus in a xeroderma pigmentosum complementation group C protein (XPC)-dependent manner, reducing the available cytoplasmic pool of this key centriole protein and preventing centrosome amplification. MDA-MB 231 cells do not express XPC and fail to move centrin into the nucleus following DNA damage. Reintroduction of XPC expression in MDA-MB 231 cells rescues nuclear centrin2 sequestration and reestablishes control against centrosome amplification, regardless of mutant p53 status. Importantly, the capacity to repair DNA damage was also dependent on the availability of centrin2 in the nucleus. These observations show that centrin and XPC cooperate in a reciprocal mechanism to coordinate centrosome homeostasis and DNA repair and suggest that this process may provide a tractable target to develop treatments to slow progression of cancer and aging.
authors.affiliation: Department of Biochemistry and Molecular Biology, Nephrology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Ilie D
authors.initials: ID
authors.lastname: Acu
authors.forename: Tieju
authors.initials: T
authors.lastname: Liu
authors.forename: Kelly
authors.initials: K
authors.lastname: Suino-Powell
authors.forename: Steven M
authors.initials: SM
authors.lastname: Mooney
authors.forename: Antonino B
authors.initials: AB
authors.lastname: D'Assoro
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rowland
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Yun
authors.initials: Y
authors.lastname: Niu
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Salisbury
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D018385:Centrosome / Q000648:ultrastructure*; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological
chemical_list: D004268:DNA-Binding Proteins; C086984:XPC protein, human
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