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AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity
- Source :
- Nature (Lond.) 592 (2021): 799–803. doi:10.1038/s41586-021-03422-5, info:cnr-pdr/source/autori:Maiani E.; Milletti G.; Nazio F.; Holdgaard S.G.; Bartkova J.; Rizza S.; Cianfanelli V.; Lorente M.; Simoneschi D.; Di Marco M.; D'Acunzo P.; Di Leo L.; Rasmussen R.; Montagna C.; Raciti M.; De Stefanis C.; Gabicagogeascoa E.; Rona G.; Salvador N.; Pupo E.; Merchut-Maya J.M.; Daniel C.J.; Carinci M.; Cesarini V.; O'sullivan A.; Jeong Y.-T.; Bordi M.; Russo F.; Campello S.; Gallo A.; Filomeni G.; Lanzetti L.; Sears R.C.; Hamerlik P.; Bartolazzi A.; Hynds R.E.; Pearce D.R.; Swanton C.; Pagano M.; Velasco G.; Papaleo E.; De Zio D.; Maya-Mendoza A.; Locatelli F.; Bartek J.; Cecconi F./titolo:AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity/doi:10.1038%2Fs41586-021-03422-5/rivista:Nature (Lond.)/anno:2021/pagina_da:799/pagina_a:803/intervallo_pagine:799–803/volume:592, Nature, Maiani, E, Milletti, G, Nazio, F, Holdgaard, S G, Bartkova, J, Rizza, S, Cianfanelli, V, Lorente, M, Simoneschi, D, Di Marco, M, D'Acunzo, P, Di Leo, L, Rasmussen, R, Montagna, C, Raciti, M, De Stefanis, C, Gabicagogeascoa, E, Rona, G, Salvador, N, Pupo, E, Merchut-Maya, J M, Daniel, C J, Carinci, M, Cesarini, V, O'sullivan, A, Jeong, Y-T, Bordi, M, Russo, F, Campello, S, Gallo, A, Filomeni, G, Lanzetti, L, Sears, R C, Hamerlik, P, Bartolazzi, A, Hynds, R E, Pearce, D R, Swanton, C, Pagano, M, Velasco, G, Papaleo, E, De Zio, D, Maya-Mendoza, A, Locatelli, F, Bartek, J & Cecconi, F 2021, ' AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity ', Nature, vol. 592, pp. 799-803 . https://doi.org/10.1038/s41586-021-03422-5
- Publication Year :
- 2021
-
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. AMBRA1-mediated degradation of cyclin D through CRL4–DDB1 regulates cell proliferation and prevents replication stress in neurodevelopment and cancer.
- Subjects :
- 0301 basic medicine
Genome instability
Cyclin D
Cyclin-Dependent Kinase
AMBRA1
medicine.disease_cause
Ambra 1
S Phase
Mice
0302 clinical medicine
Genes, Tumor Suppressor
Synthetic Lethal Mutation
Tissue homeostasis
Cyclin
Mice, Knockout
Multidisciplinary
Cell Cycle
CELL CICLE
Adaptor Proteins
Gene Expression Regulation, Developmental
Cell cycle
Cyclin-Dependent Kinases
Cell biology
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
030220 oncology & carcinogenesis
Human
DNA Replication
Settore BIO/06
Biology
Article
Genomic Instability
NO
Cell Line
03 medical and health sciences
Cyclin-dependent kinase
medicine
Animals
Humans
Settore BIO/10
Adaptor Proteins, Signal Transducing
Cell Proliferation
Cell growth
Animal
Signal Transducing
Genética
Ambra 1, S Phase, Cell Cycle, Cyclin D, Genomic Instability
030104 developmental biology
Checkpoint Kinase 1
biology.protein
AMBRA
Synthetic Lethal Mutations
Carcinogenesis
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nature (Lond.) 592 (2021): 799–803. doi:10.1038/s41586-021-03422-5, info:cnr-pdr/source/autori:Maiani E.; Milletti G.; Nazio F.; Holdgaard S.G.; Bartkova J.; Rizza S.; Cianfanelli V.; Lorente M.; Simoneschi D.; Di Marco M.; D'Acunzo P.; Di Leo L.; Rasmussen R.; Montagna C.; Raciti M.; De Stefanis C.; Gabicagogeascoa E.; Rona G.; Salvador N.; Pupo E.; Merchut-Maya J.M.; Daniel C.J.; Carinci M.; Cesarini V.; O'sullivan A.; Jeong Y.-T.; Bordi M.; Russo F.; Campello S.; Gallo A.; Filomeni G.; Lanzetti L.; Sears R.C.; Hamerlik P.; Bartolazzi A.; Hynds R.E.; Pearce D.R.; Swanton C.; Pagano M.; Velasco G.; Papaleo E.; De Zio D.; Maya-Mendoza A.; Locatelli F.; Bartek J.; Cecconi F./titolo:AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity/doi:10.1038%2Fs41586-021-03422-5/rivista:Nature (Lond.)/anno:2021/pagina_da:799/pagina_a:803/intervallo_pagine:799–803/volume:592, Nature, Maiani, E, Milletti, G, Nazio, F, Holdgaard, S G, Bartkova, J, Rizza, S, Cianfanelli, V, Lorente, M, Simoneschi, D, Di Marco, M, D'Acunzo, P, Di Leo, L, Rasmussen, R, Montagna, C, Raciti, M, De Stefanis, C, Gabicagogeascoa, E, Rona, G, Salvador, N, Pupo, E, Merchut-Maya, J M, Daniel, C J, Carinci, M, Cesarini, V, O'sullivan, A, Jeong, Y-T, Bordi, M, Russo, F, Campello, S, Gallo, A, Filomeni, G, Lanzetti, L, Sears, R C, Hamerlik, P, Bartolazzi, A, Hynds, R E, Pearce, D R, Swanton, C, Pagano, M, Velasco, G, Papaleo, E, De Zio, D, Maya-Mendoza, A, Locatelli, F, Bartek, J & Cecconi, F 2021, ' AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity ', Nature, vol. 592, pp. 799-803 . https://doi.org/10.1038/s41586-021-03422-5
- Accession number :
- edsair.doi.dedup.....9eb3a5f17bd536c3cceee8b07b588edc