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

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  • 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
  • Francesco Cecconi
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind592
Udgave nummer7856
Sider (fra-til)799-803
Antal sider5
ISSN0028-0836
DOI
StatusUdgivet - 29 apr. 2021

Bibliografisk note

Funding Information:
Acknowledgements E. Maiani is an Adjunct Professor at UniCamillus—Saint Camillus International University of Health Sciences. The F.C. laboratory is supported by grants from the Danish Cancer Society (KBVU R72-A4408, R146-A9364, R231-A14034 to F.C.; R146-A9471 to V. Cianfanelli; R146-A9414 to G.F.; R204-A12424 to D.D.Z.), the Novo Nordisk Foundation (NNF13OC0007559, NNF16OC0022544), the Lundbeck Foundation (R233-2016-3360 to F.C.; R209-2015-3505 to V. Cianfanelli), the LEO Foundation (LF17024 to F.C. and E. Papaleo; LF-OC-19-000004 to D.D.Z.), the Associazione Italiana per la Ricerca sul Cancro (AIRC project IG 2019 #23543 to F.C.; #22811 to L.L.; 5x1000 #9962 and AIRC IG 2018 #21724 to F.L.), the Italian Ministry of Research (MIUR, project PRIN 2017 FS5SHL Radius) and the Italian Ministry of Health (Ricerca Corrente to F.L. and F.N.). This work was also supported by the European Union’s Horizon 2020 research and innovation program (Marie Sklodowska-Curie grant agreement 642295 (MEL-PLEX)). D.D.Z. is supported by the Melanoma Research Alliance (MRA 620385). The F.C., J. Bartek and E. Papaleo laboratories in Copenhagen are part of the Center of Excellence for Autophagy, Recycling and Disease (CARD), funded by the Danmarks Grundforskningsfond (DNRF125). L.L. is supported by FPRC 5x1000 Ministero della Salute 2015. V. Cianfanelli, C.M. and M.B. are supported by the Fondazione Umberto Veronesi. M.P. is funded by grants from the National Institute of Health (R01-CA76584 and R35-GM136250) and is an investigator with the Howard Hughes Medical Institute; the work of E. Papaleo is supported by the Carlsberg Foundation Distinguished Fellowship (CF18-0314); work in the G.V. group is supported by the PI15/00339 grant, integrated into the State Plan for R&D + I2013-2016 and funded by the Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund (ERDF), by the Marie Skłodowska-Curie Innovative Training Network (ITN) action TRAIN (GA 721532) funded by the European Commission (H2020) and by grants from Voices Against Brain Cancer and ‘Fundació La Marató de TV3’ (20134031). J. Bartek, J. Bartkova and A.M.-M. are supported by grants from the Danish Cancer Society (R204-A12617-B153), the Novo Nordisk Foundation (16854 and 0060590), the Danish Council for Independent Research (DFF-7016-00313), the Lundbeck Foundation (R266-2017-4289), the Swedish Research Council (VR-MH 2014-46602-117891-30) and the Swedish Cancerfonden (170176). We thank P. Bonaldo and P. Braghetta for the generation of the Ambra1flox/flox mouse model, V. Turcanova for help with cloning and mutagenesis, Plaisant S.r.l. (Castel Romano) and the Danish Cancer Society animal facilities for help with in vivo experiments, V. Tocco and the FACS facility members for technical help in the flow cytometry analysis and C. Rodolfo for his help and support. G.M. is grateful to A. M. Gatta and V. Milletti for their support.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

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