The Long-Lost Ligase: CRL4(AMBRA1) Regulates the Stability of D-Type Cyclins

D-type cyclins (cyclin D1, D2, and D3, together cyclin D) are central drivers of the cell division cycle and well-described proto-oncoproteins. Rapid turnover of cyclin D is critical for its regulation, but the underlying mechanism has remained a matter of debate. Recently, AMBRA1 was identified as the major regulator of the stability of all three D-type cyclins. AMBRA1 serves as the substrate receptor for one of ∼40 CUL4-RING E3 ubiquitin ligase (CRL4) complexes to mediate the polyubiquitylation and subsequent degradation of cyclin D. Consequently, AMBRA1 regulates cell proliferation to impact tumor growth and the cellular response to cell cycle-targeted cancer therapies. Here we discuss the findings that implicate AMBRA1 as a core member of the cell cycle machinery.