Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation

Zhengcheng He, Ryan Ghorayeb, Susanna Tan, Ke Chen, Amanda C. Lorentzian, Jack Bottyan, Syed Mohammed Musheer Aalam, Miguel Angel Pujana, Philipp F. Lange, Nagarajan Kannan, Connie J. Eaves, Christopher A. Maxwell

Research output: Contribution to journalArticlepeer-review

Abstract

Preneoplastic mammary tissues from human female BRCA1 mutation carriers, or Brca1-mutant mice, display unexplained abnormalities in luminal differentiation. We now study the division characteristics of human mammary cells purified from female BRCA1 mutation carriers or non-carrier donors. We show primary BRCA1 mutant/+ cells exhibit defective BRCA1 localization, high radiosensitivity and an accelerated entry into cell division, but fail to orient their cell division axis. We also analyse 15 genetically-edited BRCA1 mutant/+ human mammary cell-lines and find that cells carrying pathogenic BRCA1 mutations acquire an analogous defect in their division axis accompanied by deficient expression of features of mature luminal cells. Importantly, these alterations are independent of accumulated DNA damage, and specifically dependent on elevated PLK1 activity induced by reduced BRCA1 function. This essential PLK1-mediated role of BRCA1 in controlling the cell division axis provides insight into the phenotypes expressed during BRCA1 tumorigenesis.

Original languageEnglish (US)
Article number2200
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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