AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity

Emiliano Maiani, Giacomo Milletti, Francesca Nazio, Søs Grønbæk Holdgaard, Jirina Bartkova, Salvatore Rizza, Valentina Cianfanelli, Mar Lorente, Daniele Simoneschi, Miriam Di Marco, Pasquale D’Acunzo, Luca Di Leo, Rikke Rasmussen, Costanza Montagna, Marilena Raciti, Cristiano De Stefanis, Estibaliz Gabicagogeascoa, Gergely Rona, Nélida Salvador, Emanuela Pupo, Joanna Maria Merchut-Maya, Colin J. Daniel, Marianna Carinci, Valeriana Cesarini, Alfie O’sullivan, Yeon-Tae Jeong, Matteo Bordi, Francesco Russo, Silvia Campello, Angela Gallo, Giuseppe Filomeni, Letizia Lanzetti, Rosalie C. Sears, Petra Hamerlik, Armando Bartolazzi, Robert E. Hynds, David R. Pearce, Charles Swanton, Michele Pagano, Guillermo Velasco, Elena Papaleo, Daniela De Zio, Apolinar Maya-Mendoza, Franco Locatelli, Jiri Bartek () and Francesco Cecconi ()
Additional contact information
Emiliano Maiani: Danish Cancer Society Research Center
Giacomo Milletti: IRCCS Bambino Gesù Children’s Hospital
Francesca Nazio: IRCCS Bambino Gesù Children’s Hospital
Søs Grønbæk Holdgaard: Danish Cancer Society Research Center
Jirina Bartkova: Danish Cancer Society Research Center
Salvatore Rizza: Danish Cancer Society Research Center
Valentina Cianfanelli: Danish Cancer Society Research Center
Mar Lorente: Complutense University
Daniele Simoneschi: NYU Grossman School of Medicine
Miriam Di Marco: Danish Cancer Society Research Center
Pasquale D’Acunzo: Nathan S. Kline Institute for Psychiatric Research
Luca Di Leo: Danish Cancer Society Research Center
Rikke Rasmussen: Danish Cancer Society Research Center
Costanza Montagna: Danish Cancer Society Research Center
Marilena Raciti: Danish Cancer Society Research Center
Cristiano De Stefanis: Research Laboratories, IRCCS Bambino Gesù Children’s Hospital
Estibaliz Gabicagogeascoa: Complutense University
Gergely Rona: NYU Grossman School of Medicine
Nélida Salvador: Complutense University
Emanuela Pupo: Candiolo Cancer Institute, FPO – IRCCS
Joanna Maria Merchut-Maya: Danish Cancer Society Research Center
Colin J. Daniel: Oregon Health & Science University
Marianna Carinci: IRCCS Bambino Gesù Children’s Hospital
Valeriana Cesarini: IRCCS Bambino Gesù Children’s Hospital
Alfie O’sullivan: NYU Grossman School of Medicine
Yeon-Tae Jeong: NYU Grossman School of Medicine
Matteo Bordi: IRCCS Bambino Gesù Children’s Hospital
Francesco Russo: Statens Serum Institut
Silvia Campello: University of Rome ‘Tor Vergata’
Angela Gallo: IRCCS Bambino Gesù Children’s Hospital
Giuseppe Filomeni: Danish Cancer Society Research Center
Letizia Lanzetti: Candiolo Cancer Institute, FPO – IRCCS
Rosalie C. Sears: Oregon Health & Science University
Petra Hamerlik: Danish Cancer Society Research Center
Armando Bartolazzi: Sant’Andrea Hospital
Robert E. Hynds: University College London
David R. Pearce: University College London
Charles Swanton: University College London
Michele Pagano: NYU Grossman School of Medicine
Guillermo Velasco: Complutense University
Elena Papaleo: Danish Cancer Society Research Center
Daniela De Zio: Danish Cancer Society Research Center
Apolinar Maya-Mendoza: Danish Cancer Society Research Center
Franco Locatelli: IRCCS Bambino Gesù Children’s Hospital
Jiri Bartek: Danish Cancer Society Research Center
Francesco Cecconi: Danish Cancer Society Research Center

Nature, 2021, vol. 592, issue 7856, 799-803

Abstract: Abstract Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel—the MYC pathway and the cyclin D–cyclin-dependent kinase (CDK)–retinoblastoma protein (RB) pathway1,2. Both MYC and the cyclin D–CDK–RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1–cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis.

Date: 2021
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DOI: 10.1038/s41586-021-03422-5

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