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<p>The oncogenic kinase AURORA A is essential for mitotic progression, and its catalytic inhibition arrests cells at the G2/M-transition. Unexpectedly, degradation of AURORA A by PROTACs (proteolysis targeting chimeras) induces profound S-phase defects, revealing a non-catalytic scaffolding function of AURORA A. To dissect this function, we profile the AURORA A S-phase interactome and identify multiple RNA-binding proteins not characterized as AURORA A substrates. Among these, the ribonuclease DICER directly associates with AURORA A to form an abundant nuclear complex. RNA degradation shifts AURORA A, DICER, and additional RNA-binding proteins from heavy to light gradient fractions, implicating RNA-dependent complex function. In contrast, PROTAC-mediated depletion of AURORA A alters the gradient migration behavior and chromatin association of the histone methyltransferase SETD2, which is known to prevent spurious transcription. These findings reveal a dual-output model for the S-phase AURORA A complex: First, RNA-binding proteins are recruited to R-loops, which may arise from transcription-replication conflicts. DICER then processes the R-loop, while AURORA A simultaneously recruits SETD2, which facilitates efficient resolution of replicative stress by preventing spurious transcription.</p>

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AURORA A interacts with DICER and SETD2 to promote S-phase progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Juliane Müller,
  • Tina Daunke,
  • Nicola Berner,
  • Pranjali Bhandare,
  • Anneli Gebhardt,
  • Lasse Hoffmann,
  • Mathias Diebold,
  • Markus Vogt,
  • Julia Hofstetter,
  • Yiliam Cruz-Garcia,
  • Nevenka Dudvarski-Stankovic,
  • Katharina Schneider,
  • Bikash Adhikari,
  • Stephanie Lamer,
  • Andreas Schlosser,
  • Gabriele Büchel,
  • Martin L Sos,
  • Bernhard Küster,
  • Stefan Knapp,
  • Stephanie Wilhelm,
  • Elmar Wolf

摘要

The oncogenic kinase AURORA A is essential for mitotic progression, and its catalytic inhibition arrests cells at the G2/M-transition. Unexpectedly, degradation of AURORA A by PROTACs (proteolysis targeting chimeras) induces profound S-phase defects, revealing a non-catalytic scaffolding function of AURORA A. To dissect this function, we profile the AURORA A S-phase interactome and identify multiple RNA-binding proteins not characterized as AURORA A substrates. Among these, the ribonuclease DICER directly associates with AURORA A to form an abundant nuclear complex. RNA degradation shifts AURORA A, DICER, and additional RNA-binding proteins from heavy to light gradient fractions, implicating RNA-dependent complex function. In contrast, PROTAC-mediated depletion of AURORA A alters the gradient migration behavior and chromatin association of the histone methyltransferase SETD2, which is known to prevent spurious transcription. These findings reveal a dual-output model for the S-phase AURORA A complex: First, RNA-binding proteins are recruited to R-loops, which may arise from transcription-replication conflicts. DICER then processes the R-loop, while AURORA A simultaneously recruits SETD2, which facilitates efficient resolution of replicative stress by preventing spurious transcription.