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

Author

Listed:
  • Emiliano Maiani

    (Danish Cancer Society Research Center
    Danish Cancer Society Research Center)

  • Giacomo Milletti

    (IRCCS Bambino Gesù Children’s Hospital
    University of Rome ‘Tor Vergata’)

  • Francesca Nazio

    (IRCCS Bambino Gesù Children’s Hospital)

  • Søs Grønbæk Holdgaard

    (Danish Cancer Society Research Center)

  • Jirina Bartkova

    (Danish Cancer Society Research Center
    Karolinska Institute)

  • Salvatore Rizza

    (Danish Cancer Society Research Center)

  • Valentina Cianfanelli

    (Danish Cancer Society Research Center
    IRCCS Bambino Gesù Children’s Hospital)

  • Mar Lorente

    (Complutense University
    Instituto de Investigación Sanitaria San Carlos (IdISSC))

  • Daniele Simoneschi

    (NYU Grossman School of Medicine
    NYU Grossman School of Medicine
    NYU Grossman School of Medicine)

  • Miriam Di Marco

    (Danish Cancer Society Research Center)

  • Pasquale D’Acunzo

    (Nathan S. Kline Institute for Psychiatric Research
    New York University School of Medicine)

  • Luca Di Leo

    (Danish Cancer Society Research Center)

  • Rikke Rasmussen

    (Danish Cancer Society Research Center)

  • Costanza Montagna

    (Danish Cancer Society Research Center
    UniCamillus—Saint Camillus International University of Health Sciences
    Copenhagen University Hospital – Bispebjerg and Frederiksberg)

  • Marilena Raciti

    (Danish Cancer Society Research Center)

  • Cristiano De Stefanis

    (Research Laboratories, IRCCS Bambino Gesù Children’s Hospital)

  • Estibaliz Gabicagogeascoa

    (Complutense University
    Instituto de Investigación Sanitaria San Carlos (IdISSC))

  • Gergely Rona

    (NYU Grossman School of Medicine
    NYU Grossman School of Medicine
    NYU Grossman School of Medicine)

  • Nélida Salvador

    (Complutense University
    Instituto de Investigación Sanitaria San Carlos (IdISSC))

  • Emanuela Pupo

    (Candiolo Cancer Institute, FPO – IRCCS)

  • Joanna Maria Merchut-Maya

    (Danish Cancer Society Research Center
    Danish Cancer Society Research Center)

  • Colin J. Daniel

    (Oregon Health & Science University)

  • Marianna Carinci

    (IRCCS Bambino Gesù Children’s Hospital
    University of Ferrara)

  • Valeriana Cesarini

    (IRCCS Bambino Gesù Children’s Hospital
    Institute of Translational Pharmacology, National Research Council of Italy (CNR))

  • Alfie O’sullivan

    (NYU Grossman School of Medicine
    NYU Grossman School of Medicine
    NYU Grossman School of Medicine)

  • Yeon-Tae Jeong

    (NYU Grossman School of Medicine
    NYU Grossman School of Medicine
    NYU Grossman School of Medicine)

  • Matteo Bordi

    (IRCCS Bambino Gesù Children’s Hospital
    University of Rome ‘Tor Vergata’)

  • Francesco Russo

    (Statens Serum Institut)

  • Silvia Campello

    (University of Rome ‘Tor Vergata’)

  • Angela Gallo

    (IRCCS Bambino Gesù Children’s Hospital)

  • Giuseppe Filomeni

    (Danish Cancer Society Research Center)

  • Letizia Lanzetti

    (Candiolo Cancer Institute, FPO – IRCCS
    University of Torino Medical School)

  • Rosalie C. Sears

    (Oregon Health & Science University
    Oregon Health & Science University)

  • Petra Hamerlik

    (Danish Cancer Society Research Center
    Copenhagen University)

  • Armando Bartolazzi

    (Sant’Andrea Hospital)

  • Robert E. Hynds

    (University College London
    The Francis Crick Institute)

  • David R. Pearce

    (University College London)

  • Charles Swanton

    (University College London
    The Francis Crick Institute)

  • Michele Pagano

    (NYU Grossman School of Medicine
    NYU Grossman School of Medicine
    NYU Grossman School of Medicine)

  • Guillermo Velasco

    (Complutense University
    Instituto de Investigación Sanitaria San Carlos (IdISSC))

  • Elena Papaleo

    (Danish Cancer Society Research Center
    University of Copenhagen)

  • Daniela De Zio

    (Danish Cancer Society Research Center)

  • Apolinar Maya-Mendoza

    (Danish Cancer Society Research Center
    Danish Cancer Society Research Center)

  • Franco Locatelli

    (IRCCS Bambino Gesù Children’s Hospital
    Sapienza University)

  • Jiri Bartek

    (Danish Cancer Society Research Center
    Karolinska Institute)

  • Francesco Cecconi

    (Danish Cancer Society Research Center
    IRCCS Bambino Gesù Children’s Hospital
    University of Rome ‘Tor Vergata’)

Abstract

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.

Suggested Citation

  • Emiliano Maiani & Giacomo Milletti & Francesca Nazio & Søs Grønbæk Holdgaard & Jirina Bartkova & Salvatore Rizza & Valentina Cianfanelli & Mar Lorente & Daniele Simoneschi & Miriam Di Marco & Pasquale, 2021. "AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity," Nature, Nature, vol. 592(7856), pages 799-803, April.
  • Handle: RePEc:nat:nature:v:592:y:2021:i:7856:d:10.1038_s41586-021-03422-5
    DOI: 10.1038/s41586-021-03422-5
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    Citations

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    Cited by:

    1. Shizhong Ke & Fabin Dang & Lin Wang & Jia-Yun Chen & Mandar T. Naik & Wenxue Li & Abhishek Thavamani & Nami Kim & Nandita M. Naik & Huaxiu Sui & Wei Tang & Chenxi Qiu & Kazuhiro Koikawa & Felipe Batal, 2024. "Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Ming Liu & Yang Wang & Fei Teng & Xinyi Mai & Xi Wang & Ming-Yuan Su & Goran Stjepanovic, 2023. "Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Bonnie Huang & James D. Phelan & Silvia Preite & Julio Gomez-Rodriguez & Kristoffer H. Johansen & Hirofumi Shibata & Arthur L. Shaffer & Qin Xu & Brendan Jeffrey & Martha Kirby & Stacie Anderson & Yan, 2022. "In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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