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1.
Nat Microbiol ; 8(11): 2154-2169, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37884813

RESUMO

Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.


Assuntos
Malária , Parasitos , Plasmodium , Animais , Malária/parasitologia , Regulação da Expressão Gênica , Plasmodium falciparum/genética
2.
Trends Genet ; 35(2): 89-92, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30477958

RESUMO

A few recent reports reveal fundamental new insights into the intricate regulatory mechanisms that govern RNA polymerase II (Pol II)-mediated gene transcription. Whereas a histidine-rich domain (HRD) triggers phase separation, promoting transcription elongation, a phosphatase switch promotes transcription termination. A paradigm that might govern the underlying mechanisms leading to robust gene transcription is now starting to emerge.


Assuntos
Cromatina/genética , Processamento de Proteína Pós-Traducional/genética , RNA Polimerase II/genética , Transcrição Gênica , Humanos , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Fator B de Elongação Transcricional Positiva/genética , Fatores de Transcrição/genética
3.
Nucleic Acids Res ; 43(6): 3033-45, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25735749

RESUMO

Despite insights on the cellular level, the molecular details of chromatin reorganization in sperm development, which involves replacement of histone proteins by specialized factors to allow ultra most condensation of the genome, are not well understood. Protamines are dispensable for DNA condensation during Drosophila post-meiotic spermatogenesis. Therefore, we analyzed the interaction of Mst77F, another very basic testis-specific protein with chromatin and DNA as well as studied the molecular consequences of such binding. We show that Mst77F on its own causes severe chromatin and DNA aggregation. An intrinsically unstructured domain in the C-terminus of Mst77F binds DNA via electrostatic interaction. This binding results in structural reorganization of the domain, which induces interaction with an N-terminal region of the protein. Via putative cooperative effects Mst77F is induced to multimerize in this state causing DNA aggregation. In agreement, overexpression of Mst77F results in chromatin aggregation in fly sperm. Based on these findings we postulate that Mst77F is crucial for sperm development by giving rise to a unique condensed chromatin structure.


Assuntos
Cromatina/química , Cromatina/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Histonas/química , Histonas/metabolismo , Animais , Animais Geneticamente Modificados , Cromatina/genética , Montagem e Desmontagem da Cromatina , DNA/química , DNA/genética , DNA/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Histonas/genética , Masculino , Mutagênese Sítio-Dirigida , Protaminas/metabolismo , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Espermatozoides/metabolismo , Eletricidade Estática
4.
Science ; 343(6166): 77-80, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24385627

RESUMO

Metaphase chromosomes are visible hallmarks of mitosis, yet our understanding of their structure and of the forces shaping them is rudimentary. Phosphorylation of histone H3 serine 10 (H3 S10) by Aurora B kinase is a signature event of mitosis, but its function in chromatin condensation is unclear. Using genetically encoded ultraviolet light-inducible cross-linkers, we monitored protein-protein interactions with spatiotemporal resolution in living yeast to identify the molecular details of the pathway downstream of H3 S10 phosphorylation. This modification leads to the recruitment of the histone deacetylase Hst2p that subsequently removes an acetyl group from histone H4 lysine 16, freeing the H4 tail to interact with the surface of neighboring nucleosomes and promoting fiber condensation. This cascade of events provides a condensin-independent driving force of chromatin hypercondensation during mitosis.


Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Mitose , Processamento de Proteína Pós-Traducional , Saccharomyces cerevisiae/metabolismo , Serina/metabolismo , Adenosina Trifosfatases/metabolismo , Cromossomos Fúngicos/genética , Cromossomos Fúngicos/metabolismo , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/efeitos da radiação , Proteínas de Ligação a DNA/metabolismo , Lisina/metabolismo , Complexos Multiproteicos/metabolismo , Fosforilação , Mapeamento de Interação de Proteínas , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Sirtuína 2/metabolismo
5.
Biochim Biophys Acta ; 1799(10-12): 810-28, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20888936

RESUMO

Chromatin modifications have gained immense significance in the past few decades as key regulators of gene expression. The enzymes responsible for these modifications along with the other non-histone proteins, remodeling factors and small RNAs modulate the chromatin dynamicity, which in turn directs the chromatin function. A concerted action of different modifying enzymes catalyzes these modifications, which are read by effector modules and converted to functional outcomes by various protein complexes. Several small molecules in the physiological system such as acetyl CoA, NAD(+), and ATP are actively involved in regulating these functional outcomes. Recent understanding in the field of epigenetics indicate the possibility of the existence of a network, 'the epigenetic language' involving cross talk among different modifications that could regulate cellular processes like transcription, replication and repair. Hence, these modifications are essential for the cellular homeostasis, and any alteration in this balance leads to a pathophysiological condition or disease manifestation. Therefore, it is becoming more evident that modulators of these modifying enzymes could be an attractive therapeutic strategy, popularly referred to as 'Epigenetic therapy.' Although this field is currently monopolized by DNA methylation and histone deacetylase inhibitors, this review highlights the modulators of the other modifications namely histone acetylation, lysine methylation and arginine methylation and argues in favor of their therapeutic potential.


Assuntos
Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Acetilcoenzima A/química , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Cromatina/química , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Ativadores de Enzimas/química , Ativadores de Enzimas/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Histonas/química , Humanos , Metilação/efeitos dos fármacos , NAD/química , NAD/metabolismo , Transcrição Gênica/efeitos dos fármacos
6.
Chem Biol ; 17(8): 903-13, 2010 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-20797619

RESUMO

Altered histone acetylation is associated with several diseases, including cancer. We report here that, unlike in most cancers, histones are found to be highly hyperacetylated in oral squamous cell carcinoma (OSCC; oral cancer) patient samples. Mechanistically, overexpression, as well as enhanced autoacetylation, of p300 induced by nucleophosmin (NPM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) causes the hyperacetylation, which is nitric oxide (NO) signal dependent. Inhibition of the histone acetyltransferase (HAT) activity of p300 by a water-soluble, small molecule inhibitor, Hydrazinocurcumin (CTK7A), substantially reduced the xenografted oral tumor growth in mice. These results, therefore, not only establish an epigenetic target for oral cancer, but also implicate a HAT inhibitor (HATi) as a potential therapeutic molecule.


Assuntos
Curcumina/análogos & derivados , Histona Acetiltransferases/antagonistas & inibidores , Histonas/metabolismo , Hidrazinas/química , Hidrazinas/farmacologia , Neoplasias Bucais/metabolismo , Óxido Nítrico/metabolismo , Água/química , Acetilação/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Células HeLa , Histona Acetiltransferases/metabolismo , Humanos , Camundongos , Camundongos Nus , Neoplasias Bucais/enzimologia , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Proteínas Nucleares/metabolismo , Nucleofosmina , Solubilidade , Regulação para Cima/efeitos dos fármacos , Fatores de Transcrição de p300-CBP/metabolismo
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