Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

Marianne S. Poruchynsky, Edina Komlodi-Pasztor, Shana Trostel, Julia Wilkerson, Marie Regairaz, Yves Pommierb, Xu Zhang, Tapan Kumar Maity, Robert Robey, Mauricio Burotto, Dan Sackettc, Udayan Guha, Antonio Tito Fojo*

*Autor correspondiente de este trabajo

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

116 Citas (Scopus)

Resumen

The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.

Idioma originalInglés
Páginas (desde-hasta)1571-1576
Número de páginas6
PublicaciónProceedings of the National Academy of Sciences of the United States of America
Volumen112
N.º5
DOI
EstadoPublicada - 3 feb. 2015
Publicado de forma externa

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