The RioK1 network determines p53 activity at multiple levels.

By responding to a host of adverse conditions, ranging from DNA damage to viral infection, transcription factor p53 supports genomic stability, cellular health, and survival. Not surprisingly, tumours across the cancer spectrum carry mutations in p53, misexpress the protein, or dysregulate its activity. Several signalling pathways, many of which comprise oncogenic proteins, converge upon p53 to control its stability and activity. We here present the conserved kinase/ATPase RioK1 as an upstream factor that determines p53 activity at the DNA, RNA, and protein levels. It achieves this task by integrating the regulatory events that act on p53 into a coherent response circuit. We will also discuss how RIOK1 overexpression represents an alternative mechanism for cancers to inactivate p53, and how targeting RioK1 could eradicate malignancies that are driven by a dysregulated RioK1-p53 network.