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



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Maiani, Emiliano and Milletti, Giacomo and Nazio, Francesca and Holdgaard, Søs Grønbæk and Bartkova, Jirina and Rizza, Salvatore and Cianfanelli, Valentina and Lorente Pérez, Mar and Simoneschi, Daniele and Di Marco, Miriam and D'Acunzo, Pasquale and Di Leo, Luca and Rasmussen, Rikke and Montagna, Costanza and Raciti, Marilena and De Stefanis, Cristiano and Gabicagogeascoa, Estíbaliz and Rona, Gergely and Salvador, Nélida and Pupo, Emanuela and Merchut-Maya, Joanna Maria and Daniel, Colin J. and Carinci, Marianna and Cesarin, Valeriana and O’sullivan, Alfie and Jeong, Yeon-Tae and Bordi, Matteo and Russo, Francesco and Campello, Silvia and Gallo, Angela and Filomeni, Giuseppe and Lanzetti, Letizia and Sears, Rosalie C. and Hamerlik, Petra and Bartolazzi, Armando and Hynds, Robert E. and Pearce, David R. and Swanton, Charles and Pagano, Michele and Velasco, Guillermo and Papaleo, Elena and Zio, Daniela De and Maya-Mendoza, Apolinar and Locatelli, Franco and Bartek, Jiri and Cecconi, Francesco (2021) AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. Nature, 592 . pp. 799-803. ISSN 1476-4687

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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.

Item Type:Article
Subjects:Medical sciences > Biology > Genetics
ID Code:65721
Deposited On:27 May 2021 19:29
Last Modified:18 Oct 2021 14:19

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