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1.
Mol Cell ; 82(13): 2458-2471.e9, 2022 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-35550257

RESUMEN

Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.


Asunto(s)
Carcinogénesis , Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica , Proteína Proto-Oncogénica c-fli-1 , Factores de Transcripción , Carcinogénesis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Silenciador del Gen , Genoma/genética , Genómica , Humanos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Oncogenes/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patología , Factores de Transcripción/genética , Transcripción Genética/genética
2.
Blood ; 137(15): 2090-2102, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33529321

RESUMEN

Friedreich ataxia (FRDA) is a frequent autosomal recessive disease caused by a GAA repeat expansion in the FXN gene encoding frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Resulting frataxin deficiency affects ISC-containing proteins and causes iron to accumulate in the brain and heart of FRDA patients. Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in cytosol and mitochondria. We observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed Tf recycling, ascribing this to impaired TfR1 palmitoylation. Frataxin deficiency is shown to reduce coenzyme A (CoA) availability for TfR1 palmitoylation. Finally, we demonstrate that artesunate, CoA, and dichloroacetate improve TfR1 palmitoylation and decrease iron overload, paving the road for evidence-based therapeutic strategies at the actionable level of TfR1 palmitoylation in FRDA.


Asunto(s)
Antígenos CD/metabolismo , Fibroblastos/patología , Ataxia de Friedreich/metabolismo , Sobrecarga de Hierro/metabolismo , Receptores de Transferrina/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Ataxia de Friedreich/complicaciones , Ataxia de Friedreich/patología , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/patología , Lipoilación , Mitocondrias/metabolismo , Mitocondrias/patología
3.
Am J Hum Genet ; 102(2): 266-277, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29395073

RESUMEN

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA.


Asunto(s)
Encéfalo/patología , Endocitosis , Hierro/metabolismo , Lipoilación , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Receptores de Transferrina/metabolismo , Secuencia de Aminoácidos , Proteínas de Unión al Calcio , Proteínas Portadoras/genética , Fibroblastos/metabolismo , Células HEK293 , Células HeLa , Homeostasis , Humanos , Mutación/genética , Receptores de Transferrina/química , Receptores de Transferrina/genética , Transferrina/metabolismo
4.
Am J Hum Genet ; 101(4): 630-637, 2017 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-28965846

RESUMEN

Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.


Asunto(s)
Ferredoxina-NADP Reductasa/genética , Pérdida Auditiva Central/genética , Proteínas Hierro-Azufre/metabolismo , Hierro/metabolismo , Enfermedades Mitocondriales/genética , Mutación , Atrofia Óptica/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Preescolar , Femenino , Ferredoxina-NADP Reductasa/química , Ferredoxina-NADP Reductasa/metabolismo , Prueba de Complementación Genética , Pérdida Auditiva Central/enzimología , Pérdida Auditiva Central/patología , Humanos , Proteínas Hierro-Azufre/genética , Masculino , Mitocondrias/enzimología , Mitocondrias/genética , Mitocondrias/patología , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/patología , Atrofia Óptica/enzimología , Atrofia Óptica/patología , Linaje , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alineación de Secuencia , Adulto Joven
5.
J Extracell Vesicles ; 11(5): e12210, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35527349

RESUMEN

Long noncoding (lnc)RNAs modulate gene expression alongside presenting unexpected source of neoantigens. Despite their immense interest, their ability to be transferred and control adjacent cells is unknown. Extracellular Vesicles (EVs) offer a protective environment for nucleic acids, with pro and antitumourigenic functions by controlling the immune response. In contrast to extracellular nonvesicular RNA, few studies have addressed the full RNA content within human fluids' EVs and have compared them with their tissue of origin. Here, we performed Total RNA-Sequencing on six Formalin-Fixed-Paraffin-Embedded (FFPE) prostate cancer (PCa) tumour tissues and their paired urinary (u)EVs to provide the first whole transcriptome comparison from the same patients. UEVs contain simplified transcriptome with intron-free cytoplasmic transcripts and enriched lnc/circular (circ)RNAs, strikingly common to an independent 20 patients' urinary cohort. Our full cellular and EVs transcriptome comparison within three PCa cell lines identified a set of overlapping 14 uEV-circRNAs characterized as essential for prostate cell proliferation in vitro and 28 uEV-lncRNAs belonging to the cancer-related lncRNA census (CLC2). In addition, we found 15 uEV-lncRNAs, predicted to encode 768 high-affinity neoantigens, and for which three of the encoded-ORF produced detectable unmodified peptides by mass spectrometry. Our dual analysis of EVs-lnc/circRNAs both in urines' and in vitro's EVs provides a fundamental resource for future uEV-lnc/circRNAs phenotypic characterization involved in PCa.


Asunto(s)
Vesículas Extracelulares , MicroARNs , Neoplasias de la Próstata , ARN Largo no Codificante , Vesículas Extracelulares/genética , Humanos , Masculino , MicroARNs/genética , Neoplasias de la Próstata/genética , ARN Circular , ARN Largo no Codificante/genética , Transcriptoma
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