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