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

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1571-1576
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number5
DOIs
StatePublished - 3 Feb 2015
Externally publishedYes

Keywords

  • Combination chemotherapy,targeted therapies
  • DNA-damaging agents
  • Dna repair protein trafficking
  • Microtubule targeting agents

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