2026-06-27T23:15:57Zhttps://docta.ucm.es/rest/oai/request
oai:docta.ucm.es:20.500.14352/81592024-09-27T17:10:58Zcom_20.500.14352_14col_20.500.14352_15
Docta Complutense author Maiani, Emiliano author Milletti, Giacomo author Nazio, Francesca author Holdgaard, Søs Grønbæk author Bartkova, Jirina author Rizza, Salvatore author Cianfanelli, Valentina author Lorente Pérez, María Del Mar author Simoneschi, Daniele author Di Marco, Miriam author D'Acunzo, Pasquale author Di Leo, Luca author Rasmussen, Rikke author Montagna, Costanza author Raciti, Marilena author De Stefanis, Cristiano author Gabicagogeascoa, Estíbaliz author Rona, Gergely author Salvador, Nélida author Pupo, Emanuela author Merchut-Maya, Joanna Maria author Daniel, Colin J. author Carinci, Marianna author Cesarin, Valeriana author O’sullivan, Alfie author Jeong, Yeon-Tae author Bordi, Matteo author Russo, Francesco author Campello, Silvia author Gallo, Angela author Filomeni, Giuseppe author Lanzetti, Letizia author Sears, Rosalie C. author Hamerlik, Petra author Bartolazzi, Armando author Hynds, Robert E. author Pearce, David R. author Swanton, Charles author Pagano, Michele author Velasco, Guillermo author Papaleo, Elena author Zio, Daniela De author Maya-Mendoza, Apolinar author Locatelli, Franco author Bartek, Jiri author Cecconi, Francesco 2023-06-17T09:05:48Z 2023-06-17T09:05:48Z 2021-04-14 1476-4687 10.1038/s41586-021-03422-5 https://hdl.handle.net/20.500.14352/8159 https://www.nature.com/articles/s41586-021-03422-5 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. eng AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity journal article URL https://docta.ucm.es/bitstreams/15bf8724-a827-4221-bcff-4c834f1df77c/download File MD5 004a87c56564542f52f335d06728e9ce 44167966 application/pdf Lorente-DGFM-AMBRA1.pdf URL https://docta.ucm.es/bitstreams/d4ed7a8d-68ba-4f24-9da1-3c3d39962264/download File MD5 e7cde6e69b2239922d23f50c5f52293f 74204 text/plain Lorente-DGFM-AMBRA1.pdf.txt