CRL4AMBRA1 is a master regulator of D-type cyclins

Nature. 2021 Apr;592(7856):789-793. doi: 10.1038/s41586-021-03445-y.

Daniele Simoneschi ¹ ², Gergely Rona ¹ ² ³, Nan Zhou ⁴, Yeon-Tae Jeong ¹ ², Shaowen Jiang ¹ ², Giacomo Milletti ⁵ ⁶, Arnaldo A Arbini ² ⁷, Alfie O'Sullivan ¹ ², Andrew A Wang ¹ ², Sorasicha Nithikasem ¹ ², Sarah Keegan ¹ ² ⁸, Yik Siu ¹, Valentina Cianfanelli ⁵ ⁹, Emiliano Maiani ⁹ ¹⁰, Francesca Nazio ⁵, Francesco Cecconi ⁵ ⁶ ⁹, Francesco Boccalatte ² ⁷, David Fenyö ¹ ² ⁸, Drew R Jones ¹, Luca Busino ¹¹, Michele Pagano ¹² ¹³ ¹⁴

Affiliations

1 Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
2 Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA.
3 Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA.
4 Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
5 Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
6 Department of Biology, University of Rome Tor Vergata, Rome, Italy.
7 Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
8 Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA.
9 Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.
10 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark.
11 Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. businol@upenn.edu.
12 Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA. michele.pagano@nyulangone.org.
13 Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA. michele.pagano@nyulangone.org.
14 Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA. michele.pagano@nyulangone.org.

PMID: 33854235 DOI: 10.1038/s41586-021-03445-y

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 debated^2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4^AMBRA1 (also known as CRL4^DCAF3) 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.

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