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

  • Nature. 2021 Apr;592(7856):799-803. doi: 10.1038/s41586-021-03422-5.
Emiliano Maiani  #  1  2 ,  Giacomo Milletti  #  3  4 ,  Francesca Nazio  3 ,  Søs Grønbæk Holdgaard  1 ,  Jirina Bartkova  5  6 ,  Salvatore Rizza  7 ,  Valentina Cianfanelli  1  3 ,  Mar Lorente  8  9 ,  Daniele Simoneschi  10  11  12 ,  Miriam Di Marco  2 ,  Pasquale D'Acunzo  13  14 ,  Luca Di Leo  15 ,  Rikke Rasmussen  16 ,  Costanza Montagna  7  17  18 ,  Marilena Raciti  1 ,  Cristiano De Stefanis  19 ,  Estibaliz Gabicagogeascoa  8  9 ,  Gergely Rona  10  11  12 ,  Nélida Salvador  8  9 ,  Emanuela Pupo  20 ,  Joanna Maria Merchut-Maya  5  21 ,  Colin J Daniel  22 ,  Marianna Carinci  3  23 ,  Valeriana Cesarini  3  24 ,  Alfie O'sullivan  10  11  12 ,  Yeon-Tae Jeong  10  11  12 ,  Matteo Bordi  3  4 ,  Francesco Russo  25 ,  Silvia Campello  4 ,  Angela Gallo  3 ,  Giuseppe Filomeni  7 ,  Letizia Lanzetti  20  26 ,  Rosalie C Sears  22  27 ,  Petra Hamerlik  16  28 ,  Armando Bartolazzi  29 ,  Robert E Hynds  30  31 ,  David R Pearce  30 ,  Charles Swanton  30  31 ,  Michele Pagano  10  11  12 ,  Guillermo Velasco  8  9 ,  Elena Papaleo  2  32 ,  Daniela De Zio  15 ,  Apolinar Maya-Mendoza  5  21 ,  Franco Locatelli  3  33 ,  Jiri Bartek  34  35 ,  Francesco Cecconi  36  37  38
Affiliations
  • 1. Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 2. Computational Biology Laboratory, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 3. Department of Pediatric Onco-Hematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • 4. Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
  • 5. Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 6. Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
  • 7. Redox Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 8. Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, Madrid, Spain.
  • 9. Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.
  • 10. Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
  • 11. Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA.
  • 12. Howard Hughes Medical Institute, NYU Grossman School of Medicine, New York, NY, USA.
  • 13. Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • 14. Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
  • 15. Melanoma Research Team, Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 16. Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 17. UniCamillus-Saint Camillus International University of Health Sciences, Rome, Italy.
  • 18. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
  • 19. Research Laboratories, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
  • 20. Candiolo Cancer Institute, FPO - IRCCS, Turin, Italy.
  • 21. DNA Replication and Cancer Group, Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 22. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
  • 23. Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
  • 24. Department of Biomedical Sciences, Institute of Translational Pharmacology, National Research Council of Italy (CNR), Rome, Italy.
  • 25. Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
  • 26. Department of Oncology, University of Torino Medical School, Turin, Italy.
  • 27. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 28. Department of Drug Design and Pharmacology, Copenhagen University, Copenhagen, Denmark.
  • 29. Department of Pathology and Pathology Research Laboratory, Sant'Andrea Hospital, Rome, Italy.
  • 30. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, UK.
  • 31. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
  • 32. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 33. Department of Gynecology-Obstetrics and Pediatrics, Sapienza University, Rome, Italy.
  • 34. Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark. [email protected].
  • 35. Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden. [email protected].
  • 36. Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark. [email protected].
  • 37. Department of Pediatric Onco-Hematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. [email protected].
  • 38. Department of Biology, University of Rome 'Tor Vergata', Rome, Italy. [email protected].
  • # Contributed equally.
PMID: 33854232 DOI: 10.1038/s41586-021-03422-5
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.