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

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.