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1.
Nature ; 592(7856): 799-803, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33854232

RESUMO

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.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Ciclina D/metabolismo , Instabilidade Genômica , Fase S , Animais , Linhagem Celular , Proliferação de Células , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Replicação do DNA , Regulação da Expressão Gênica no Desenvolvimento , Genes Supressores de Tumor , Humanos , Camundongos , Camundongos Knockout , Mutações Sintéticas Letais
2.
Autophagy ; 16(2): 379-381, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31847687

RESUMO

The selective clearance of cellular components by macroautophagy (hereafter autophagy) is critical for maintaining cellular homeostasis. In this punctum, we summarize and discuss our recent findings regarding a novel type of selective autophagy that targets centriolar satellites (CS) for degradation, a process we termed doryphagy from the Greek word "doryphoros", standing for "satellite". CS are microtubule-associated protein complexes that regulate centrosome composition. We show that CS degradation is mediated through a direct interaction between GABARAPs and an LC3-interacting region (LIR) motif in the CS protein PCM1. Autophagy-deficient systems accumulate large abnormal CS and consequently display centrosome reorganization and abnormal mitoses. Our findings provide a mechanistic link between autophagy deficiency and centrosome abnormalities and exemplify how mammalian Atg8-family proteins (mATG8s) can regulate substrate specificity.


Assuntos
Autofagia , Centríolos/metabolismo , Animais , Humanos , Microtúbulos/metabolismo , Mitose , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Proteólise , Especificidade por Substrato
3.
Nat Commun ; 10(1): 4176, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519908

RESUMO

The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in cancer, but little is known of their origin and about pathways affecting centrosome homeostasis. Here we show that autophagy preserves centrosome organization and stability through selective turnover of centriolar satellite components, a process we termed doryphagy. Autophagy targets the satellite organizer PCM1 by interacting with GABARAPs via a C-terminal LIR motif. Accordingly, autophagy deficiency results in accumulation of large abnormal centriolar satellites and a resultant dysregulation of centrosome composition. These alterations have critical impact on centrosome stability and lead to mitotic centrosome fragmentation and unbalanced chromosome segregation. Our findings identify doryphagy as an important centrosome-regulating pathway and bring mechanistic insights to the link between autophagy dysfunction and chromosomal instability. In addition, we highlight the vital role of centriolar satellites in maintaining centrosome integrity.


Assuntos
Autofagia/fisiologia , Centríolos/metabolismo , Centrossomo/metabolismo , Mitose/fisiologia , Autofagia/genética , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Cromatografia Líquida , Humanos , Immunoblotting , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Microscopia de Fluorescência , Microtúbulos/metabolismo , Mitose/genética , Simulação de Dinâmica Molecular
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