10 documents found, page 1 of 1
CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells
Mensurado, Sofia; Condeço, Carolina; Sánchez-Martínez, Diego; Shirley, Sara; Coelho, Rui; Tirado, Néstor; Vinyoles, Meritxell; Blanco Dominguez, RafaelRelapsed or refractory acute myeloid leukemia (AML) remains a major therapeutic challenge. We have recently developed a Vδ1+ γδ T cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells r...
Genetic modulation of RNA splicing rescues BRCA2 function in mutant cells
Lima, Beatriz Anjo; Pais, Ana Carolina; Dupont, Juliette; Dias, Patrícia; Custódio, Noélia; Sousa, Ana Berta; Carmo-Fonseca, Maria; Carvalho, CéliaVariants in the hereditary cancer-associated BRCA1 and BRCA2 genes can alter RNA splicing, producing transcripts that encode internally truncated yet potentially functional proteins. However, few studies have quantitatively analyzed variant-specific splicing isoforms. Here, we investigated cells heterozygous and homozygous for the BRCA2:c.681+5G>C variant. Using droplet digital RT-PCR, we identified two variant...
RP-10 LESSONS FROM THE COVID-19 PANDEMIC: STUDENT EVALUATION OF A NEWLY IMPLEME...
Velha, António; Custódio, Noélia; Carmo-Fonseca, Maria; Patrício, MadalenaIntroduction and goal As the COVID-19 pandemic flooded the world throughout the first half of 2020, medical schools were faced with a choice: swim or die – learning shifted radically online as countries went into lockdown. With the easing of restrictions, the Molecular and Cellular Biology (MCB) course at FMUL introduced a flipped classroom approach during semester I, based on pre-recorded lectures followed by ...
Expression profiling in ovarian cancer reveals coordinated regulation of BRCA1/...
Custódio, Noélia; Savisaar, Rosina; Carvalho, Célia; Bak-Gordon, Pedro; Ribeiro, Maria I.; Almeida-Tavares, Joana; Nunes, Paula B.; Peixoto, CarolinaPredictive biomarkers are crucial in clarifying the best strategy to use poly(ADP-ribose) polymerase inhibitors (PARPi) for the greatest benefit to ovarian cancer patients. PARPi are specifically lethal to cancer cells that cannot repair DNA damage by homologous recombination (HR), and HR deficiency is frequently associated with BRCA1/2 mutations. Genetic tests for BRCA1/2 mutations are currently used in the cl...
Deep intronic mutations and human disease
Vaz-Drago, Rita; Custódio, Noélia; Carmo-Fonseca, MariaNext-generation sequencing has revolutionized clinical diagnostic testing. Yet, for a substantial proportion of patients, sequence information restricted to exons and exon-intron boundaries fails to identify the genetic cause of the disease. Here we review evidence from mRNA analysis and entire genomic sequencing indicating that pathogenic mutations can occur deep within the introns of over 75 disease-associate...
Co-transcriptional splicing and the CTD code
Custódio, Noélia; Carmo-Fonseca, MariaTranscription and splicing are fundamental steps in gene expression. These processes have been studied intensively over the past four decades, and very recent findings are challenging some of the formerly established ideas. In particular, splicing was shown to occur much faster than previously thought, with the first spliced products observed as soon as splice junctions emerge from RNA polymerase II (Pol II). S...
A link between nuclear RNA surveillance, the human exosome and RNA polymerase I...
Almeida, Sérgio F. de; García-Sacristán, Ana; Custódio, Noélia; Carmo-Fonseca, MariaIn eukaryotes, the production of mature messenger RNA that exits the nucleus to be translated into protein in the cytoplasm requires precise and extensive modification of the nascent transcript. Any failure that compromises the integrity of an mRNA may cause its retention in the nucleus and trigger its degradation. Multiple studies indicate that mRNAs with processing defects accumulate in nuclear foci or ‘dots’...
Quality control of gene expression in the mammalian cell nucleus
Custódio, NoéliaProtein-encoding genes are transcribed in the nucleus by RNA polymerase II as precursor RNAs that undergo extensive processing before being translocated to the cytoplasm for translation by the ribosomes. This spatial and temporal separation between RNA and protein synthesis offers an immense opportunity for regulation and quality control.When this study was initiated it was known from biochemical studies that h...
Abundance of the largest subunit of RNA polymerase II in the nucleus is regulat...
Custódio, Noélia; Antoniou, Michael; Carmo-Fonseca, MariaEukaryotic RNA polymerase II is a complex enzyme composed of 12 distinct subunits that is present in cells in low abundance. Transcription of mRNA by RNA polymerase II involves a phosphorylation/dephosphorylation cycle of the carboxyl-terminal domain (CTD) of the enzyme's largest subunit. We have generated stable murine cell lines expressing an alpha-amanitin-resistant form of the largest subunit of RNA polymer...
In vivo recruitment of exon junction complex proteins to transcription sites in...
Custódio, Noélia; Carvalho, Célia; Condado, Inês; Antoniou, Michael; Blencowe, Benjamin J.; Carmo-Fonseca, MariaStudies over the past years indicate that there is extensive coupling between nuclear export of mRNA and pre-mRNA processing. Here, we visualized the distribution of exon junction complex (EJC) proteins and RNA export factors relative to sites of abundant pre-mRNA synthesis in the nucleus. We analyzed both HeLa cells infected with adenovirus and murine erythroleukemia (MEL) cells stably transfected with the hum...