CRL4AMBRA1 is a master regulator of D-type cyclins

Daniele Simoneschi, Gergely Rona, Nan Zhou, Yeon-Tae Jeong, Shaowen Jiang, Giacomo Milletti, Arnaldo A. Arbini, Alfie O’Sullivan, Andrew A. Wang, Sorasicha Nithikasem, Sarah Keegan, Yik Siu, Valentina Cianfanelli, Emiliano Maiani, Francesca Nazio, Francesco Cecconi, Francesco Boccalatte, David Fenyö, Drew R. Jones, Luca Busino () and Michele Pagano ()
Additional contact information
Daniele Simoneschi: NYU Grossman School of Medicine
Gergely Rona: NYU Grossman School of Medicine
Nan Zhou: University of Pennsylvania Perelman School of Medicine
Yeon-Tae Jeong: NYU Grossman School of Medicine
Shaowen Jiang: NYU Grossman School of Medicine
Giacomo Milletti: IRCCS Bambino Gesù Children’s Hospital
Arnaldo A. Arbini: NYU Grossman School of Medicine
Alfie O’Sullivan: NYU Grossman School of Medicine
Andrew A. Wang: NYU Grossman School of Medicine
Sorasicha Nithikasem: NYU Grossman School of Medicine
Sarah Keegan: NYU Grossman School of Medicine
Yik Siu: NYU Grossman School of Medicine
Valentina Cianfanelli: IRCCS Bambino Gesù Children’s Hospital
Emiliano Maiani: Danish Cancer Society Research Center
Francesca Nazio: IRCCS Bambino Gesù Children’s Hospital
Francesco Cecconi: IRCCS Bambino Gesù Children’s Hospital
Francesco Boccalatte: NYU Grossman School of Medicine
David Fenyö: NYU Grossman School of Medicine
Drew R. Jones: NYU Grossman School of Medicine
Luca Busino: University of Pennsylvania Perelman School of Medicine
Michele Pagano: NYU Grossman School of Medicine

Nature, 2021, vol. 592, issue 7856, 789-793

Abstract: Abstract D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR–Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.

Date: 2021
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DOI: 10.1038/s41586-021-03445-y

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