RESUMO
Amino acid deprivation or supplementation can affect cellular and organismal life span, but we know little about the role of concentration changes in free, intracellular amino acids during aging. Here, we determine free amino acid levels during chronological aging of nondividing fission yeast cells. We compare wild-type with long-lived mutant cells that lack the Pka1 protein of the protein kinase A signalling pathway. In wild-type cells, total amino acid levels decrease during aging, but much less so in pka1 mutants. Two amino acids strongly change as a function of age: glutamine decreases, especially in wild-type cells, while aspartate increases, especially in pka1 mutants. Supplementation of glutamine is sufficient to extend the chronological life span of wild-type but not of pka1Δ cells. Supplementation of aspartate, on the other hand, shortens the life span of pka1Δ but not of wild-type cells. Our results raise the possibility that certain amino acids are biomarkers of aging, and their concentrations during aging can promote or limit cellular life span.
Assuntos
Aminoácidos/metabolismo , Schizosaccharomyces/metabolismo , Ácido Aspártico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glutamina/metabolismo , Mutação , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Transdução de SinaisRESUMO
Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis, and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3, and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.
Assuntos
Rearranjo Gênico , Predisposição Genética para Doença , Histona Acetiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Apoptose/genética , Biomarcadores Tumorais , Diferenciação Celular , Linhagem Celular Tumoral , Gerenciamento Clínico , Epigênese Genética , Técnicas de Inativação de Genes , Estudos de Associação Genética , Histona Acetiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Células Mieloides/metabolismo , Células Mieloides/patologia , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Regiões Promotoras Genéticas , Ligação ProteicaRESUMO
Qu et al. (2020) demonstrate a peptide-induced targeted degradation of the alpha-synuclein protein, a hallmark of Parkinson's disease. Using a modular three-component design, the target-protein-specific, cell-permeable peptide disposed of alpha-synuclein via the ubiquitin-proteasome pathway rather than the standard autophagy-lysosome pathway.
Assuntos
Complexo de Endopeptidases do Proteassoma , alfa-Sinucleína , AutofagiaRESUMO
Point-of-care (PoC) diagnostics promises to yield test results accessible anytime and anywhere. Its application has expanded from providing healthcare necessities to the real-time monitoring of the ageing and health conscious population. Following the evolving consumer demand, there is a trend toward developing non- and minimally invasive PoC tests. Emerging PoC sensors have not only demonstrated multifunctional capabilities such as sweat stimulation but also can be connected to drug delivery units via a wireless network, enabling an active role of the technology in disease management. This review article summarises the latest developments in non- and minimally invasive PoC diagnostics and provides an overview on the progress towards closed-loop integration of complementary technologies for comprehensive and autonomous patient care.