Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros

Base de dados
Tipo de documento
Assunto da revista
País de afiliação
Intervalo de ano de publicação
1.
Genes Dev ; 27(15): 1680-92, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23884607

RESUMO

The conversion of male germ cell chromatin to a nucleoprotamine structure is fundamental to the life cycle, yet the underlying molecular details remain obscure. Here we show that an essential step is the genome-wide incorporation of TH2B, a histone H2B variant of hitherto unknown function. Using mouse models in which TH2B is depleted or C-terminally modified, we show that TH2B directs the final transformation of dissociating nucleosomes into protamine-packed structures. Depletion of TH2B induces compensatory mechanisms that permit histone removal by up-regulating H2B and programming nucleosome instability through targeted histone modifications, including lysine crotonylation and arginine methylation. Furthermore, after fertilization, TH2B reassembles onto the male genome during protamine-to-histone exchange. Thus, TH2B is a unique histone variant that plays a key role in the histone-to-protamine packing of the male genome and guides genome-wide chromatin transitions that both precede and follow transmission of the male genome to the egg.


Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Protaminas/metabolismo , Animais , Epigênese Genética , Feminino , Fertilização/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Histonas/genética , Masculino , Meiose , Camundongos , Nucleossomos , Espermatogênese/genética , Testículo/metabolismo
2.
Biochim Biophys Acta ; 1829(10): 1010-4, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23831842

RESUMO

BACKGROUND: Unscheduled expression of critical cellular regulators could be central to malignant genome reprogramming and tumor establishment. One such factor appears to be ATAD2, a remarkably conserved protein normally predominantly expressed in germ cells but almost systematically over-expressed in a variety of unrelated cancers. The presence of a bromodomain adjacent to an AAA type ATPase domain, points to ATAD2 as a factor preliminarily acting on chromatin structure and function. Accordingly, ATAD2 has been shown to cooperate with a series of transcription factors and chromatin modifiers to regulate specific set of genes. SCOPE OF REVIEW: Here we discuss our knowledge on ATAD2 to evaluate its role as a cancer driver and its value as a new anti-cancer target. MAJOR CONCLUSIONS: Upon its activation, ATAD2 through its interaction with defined transcription factors, initiates a loop of transcriptional stimulation of target genes, including ATAD2 itself, leading to enhanced cell proliferation and resistance to apoptosis in an ATAD2-dependent manner. Approaches aiming at neutralizing ATAD2 activity in cancer, including the use of small molecule inhibitors of its two "druggable" domains, AAA ATPase and bromodomain, could become part of a promising anti-cancer strategy.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Genoma Humano , Neoplasias/genética , ATPases Associadas a Diversas Atividades Celulares , Humanos
3.
Life Sci Alliance ; 4(12)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34580178

RESUMO

Taking advantage of the evolutionary conserved nature of ATAD2, we report here a series of parallel functional studies in human, mouse, and Schizosaccharomyces pombe to investigate ATAD2's conserved functions. In S. pombe, the deletion of ATAD2 ortholog, abo1, leads to a dramatic decrease in cell growth, with the appearance of suppressor clones recovering normal growth. The identification of the corresponding suppressor mutations revealed a strong genetic interaction between Abo1 and the histone chaperone HIRA. In human cancer cell lines and in mouse embryonic stem cells, we observed that the KO of ATAD2 leads to an accumulation of HIRA. A ChIP-seq mapping of nucleosome-bound HIRA and FACT in Atad2 KO mouse ES cells demonstrated that both chaperones are trapped on nucleosomes at the transcription start sites of active genes, resulting in the abnormal presence of a chaperone-bound nucleosome on the TSS-associated nucleosome-free regions. Overall, these data highlight an important layer of regulation of chromatin dynamics ensuring the turnover of histone-bound chaperones.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Chaperonas de Histonas/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Nucleossomos/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , Animais , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Deleção de Genes , Técnicas de Inativação de Genes , Genótipo , Células HeLa , Células Hep G2 , Humanos , Camundongos , Microrganismos Geneticamente Modificados , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Transfecção
4.
J Mol Cell Biol ; 8(4): 349-62, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26459632

RESUMO

Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells Atad2 becomes critical in sustaining specific gene expression programmes, controlling proliferation and differentiation. Altogether, this work defines Atad2 as a facilitator of general chromatin-templated activities such as transcription.


Assuntos
Adenosina Trifosfatases/metabolismo , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Acetilação , Diferenciação Celular , Proliferação de Células , Imunoprecipitação da Cromatina , Células-Tronco Embrionárias/citologia , Genoma , Células Germinativas/metabolismo , Humanos , Masculino , Nucleossomos/metabolismo , Ligação Proteica , Proteômica
5.
Mol Cells ; 37(12): 851-6, 2014 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-25377252

RESUMO

ATAD2, a remarkably conserved, yet poorly characterized factor is found upregulated and associated with poor prognosis in a variety of independent cancers in human. Studies conducted on the yeast Saccharomyces cerevisiae ATAD2 homologue, Yta7, are now indicating that the members of this family may primarily be regulators of chromatin dynamics and that their action on gene expression could only be one facet of their general activity. In this review, we present an overview of the literature on Yta7 and discuss the possibility of translating these findings into other organisms to further define the involvement of ATAD2 and other members of its family in regulating chromatin structure and function both in normal and pathological situations.


Assuntos
Adenosina Trifosfatases/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Regulação da Expressão Gênica , Genoma Fúngico , Genoma Humano , Chaperonas de Histonas/metabolismo , Humanos , Filogenia , Saccharomyces cerevisiae/genética , Ativação Transcricional
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA