RT Journal Article
T1 AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity
A1 Maiani, Emiliano
A1 Milletti, Giacomo
A1 Nazio, Francesca
A1 Holdgaard, Søs Grønbæk
A1 Bartkova, Jirina
A1 Rizza, Salvatore
A1 Cianfanelli, Valentina
A1 Lorente Pérez, Mar
A1 Simoneschi, Daniele
A1 Di Marco, Miriam
A1 D'Acunzo, Pasquale
A1 Di Leo, Luca
A1 Rasmussen, Rikke
A1 Montagna, Costanza
A1 Raciti, Marilena
A1 De Stefanis, Cristiano
A1 Gabicagogeascoa, Estíbaliz
A1 Rona, Gergely
A1 Salvador, Nélida
A1 Pupo, Emanuela
A1 Merchut-Maya, Joanna Maria
A1 Daniel, Colin J.
A1 Carinci, Marianna
A1 Cesarin, Valeriana
A1 O’sullivan, Alfie
A1 Jeong, Yeon-Tae
A1 Bordi, Matteo
A1 Russo, Francesco
A1 Campello, Silvia
A1 Gallo, Angela
A1 Filomeni, Giuseppe
A1 Lanzetti, Letizia
A1 Sears, Rosalie C.
A1 Hamerlik, Petra
A1 Bartolazzi, Armando
A1 Hynds, Robert E.
A1 Pearce, David R.
A1 Swanton, Charles
A1 Pagano, Michele
A1 Velasco, Guillermo
A1 Papaleo, Elena
A1 Zio, Daniela De
A1 Maya-Mendoza, Apolinar
A1 Locatelli, Franco
A1 Bartek, Jiri
A1 Cecconi, Francesco
AB 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.
PB Nature Research
SN 1476-4687
YR 2021
FD 2021-04-14
LK https://hdl.handle.net/20.500.14352/8159
UL https://hdl.handle.net/20.500.14352/8159
LA eng
NO Unión Europea. Horizonte 2020
NO Instituto de Salud Carlos III (ISCIII)/FEDER
NO Danish Cancer Society
NO Novo Nordisk Foundation
NO Lundbeck Foundation
NO LEO Foundation
NO Associazione Italiana per la Ricerca sul Cancro (AIRC)
NO Italian Ministry of Research (MIUR)
NO Italian Ministry of Health
NO Melanoma Research Alliance
NO Center of Excellence for Autophagy, Recycling and Disease (CARD)
NO Ministero della Salute
NO Fondazione Umberto Veronesi
NO National Institute of Health
NO Howard Hughes Medical Institute
NO Carlsberg Foundation Distinguished Fellowship
NO Voices Against Brain Cancer
NO Fundació La Marató de TV3
NO Danish Council for Independent Research
NO Swedish Research Council
NO Swedish Cancerfonden
DS Docta Complutense
RD 27 abr 2024