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.
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| http://dx.doi.org/10.1089/dna.2021.0659 | DOI Listing |
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Article Synopsis
- * D-type cyclins are recruited to oxidative damage sites, protecting p21 from degradation, which in turn blocks MMR by competing with MMR components for binding to PCNA.
- * The degradation of D-type cyclins at the G1/S transition is crucial for allowing MMR proteins to interact with PCNA, ensuring proper repair of DNA replication errors; however, persistent cyclin D1 during S-phase can increase mutation rates.
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