Visão | Cancro - A corrida pelas vacinas

October 13, 2022

Read here (Portuguese only).

RTP3 | Grande Entrevista

August 17, 2022

Watch here (Portuguese only).

Público | "O ARN e o ADN formam nós que determinam o destino das células"

June 6, 2022

Read here (Portuguese only).

Expresso | "Cientistas portugueses realçam importância de primeiro genoma humano completo"

March 31, 2022

Read here (Portuguese only).

Expresso | "mRNA, a arma que está a revolucionar a saúde"

February 28, 2022

Read here (Portuguese only).

Público | "Estamos a entrar na era dos medicamentos de ARN e ADN"

November 2, 2021

Read here the interview with Melissa Moore, member of RiboMed Advisory Board (Portuguese only).

RNA Society | Member Spotlight: Professor Maria Carmo-Fonseca by Rui Flu

October 2021

Read here.

SAPO24 | mRNA: Dos bastidores ao palco principal do combate à pandemia. As vacinas contra a COVID-19 são só a ponta do iceberg

August 2, 2021

Read here (Portuguese only).

RTP1 - Jornal da Tarde | RNA Vaccines

July 3, 2021

Watch here (Portuguese only).

Observador | Found technology that can help understand diseases

June 16, 2021

Instituto de Medicina Molecular and Oxford University develop a mechanism to better understand DNA and RNA. Certain diseases can occur due to defects between these two chains.

Read more here (Portuguese only).

Público | Portuguese help create a new technique that deciphers the speech of our cells

June 14, 2021

A team with scientists from the Instituto de Medicina Molecular has developed a new technology to understand the dynamics of RNA and which can help in the understanding of certain diseases.

Read more here (Portuguese only).

SIC - Admirável Mundo Novo | RNA – a new era in cancer treatment and new way to revert ageing

December 28, 2020

Maria-Carmo Fonseca, RiboMed coordinator, iMM President and Group leader, and RNA Society President, nominate RNA molecule as the most important scientific event of 2020: because of the SARS-CoV virus for sure, but mainly because of the new RNA vaccines and for the Nobel Prize in Chemistry awarded to CRIPSR technology.

Maria-Carmo Fonseca also emphasizes the important of Science and the joint efforts of scientist through this year to fight COVID-19 pandemic that culminate in the vaccine in less than a year. The principles applied to the SARS-CoV-2 vaccine can be used in cancer treatments.

Read more here (Portuguese only).

Visão | mRNA, the Theraphy of the Future

November 19, 2020

Over the last few weeks promising data on SARS-COV-2 vaccines efficacy were publicized. Some of those vaccines are innovative and based on mensager RNA (mRNA).

The journalists Mariana Almeida Nogueira e Vânia Maia wrote in Revista Visão a piece that explain the importance of the approval of first vaccines based on mRNA.

One of the personalities interviewed in that work in Maria-Carmo Fonseca, president of the Instituto de Medicina Molecular and RNA Society and RiboMed coordinator. Maria-Carmo Fonseca emphasizes the important moment we are all living and the potential therapies based on RNA. The researcher highlights also that the team that coordinates “is focused on cardiac diseases with genetic causes that can lead to sudden dead, and that can be corrected by RNA. Almost all the genetic diseases drove from damaged original information that pass from DNA to RNA; however, now is possible to correct those mistakes at RNA level, without need to alter the DNA.”

Read more here (Portuguese only).

Exame Informática | Maria-Carmo Fonseca election as President of The RNA Society

September 1, 2020

On May 2020, Maria-Carmo Fonseca, RiboMed coordinator and President of Instituto de Medicina Molecular, was elected the new President of The RNA Society.

The RNA Society is an international scientific society dedicated to fostering research and education in the field of RNA science. This Society, with more than 1800 members, is a community of scientists passionate about better understanding the fascinating world of RNA biology.

Read more here (Portuguese only).

Academia das Ciências Médicas de Lisboa

March 3, 2022

"RNA in medicine"

On 3rd March 2022 Maria-Carmo Fonseca, RiboMed coordinator, and iMM principal researcher, discussed the RNA in medicine at the Academia das Ciências Médicas de Lisboa.

"In the early 1950s, the discovery of the DNA double helix triggered the rapid development of an emerging scientific area termed Molecular Biology. Since the birth of recombinant DNA technology, the science of Biology and Genetics changed from studying “Life as we know it”, to “Life as we make it”. With the turn of the millennium, a new revolution in the Life Sciences started to take shape and at the beginning of the 2020s, the potential impact of RNA molecules in medicine is huge. From RNA interference therapies, to mRNA vaccines and CRISPR-mediated genome editing, my conference will focus on the brave new world of medical applications of RNA."

International Nucleome Consortium Webinar

July 17, 2020

"The challenge of measuring splicing kinetics" by M. Carmo-Fonseca

New Frontiers in Cardiomyopathies. Cardiomyopathies in clinical practice. International Post-Graduate Learning Course.

November 28-29, 2019

The "New Frontiers in Cardiomyopathies – Cardiomyopathies in clinical practice" was a live educational event directed by Dulce Brito, MD, Ph.D and Fausto J. Pinto, MD, Ph.D in Lisbon School of Medicine, Universidade de Lisboa, Portugal. This course aimed to provide up-to-date knowledge of cardiomyopathies regarding the mechanisms involved in their development and progression, how to diagnose and manage, how to choose the best candidates for new or specific therapies.

In this course, Maria-Carmo Fonseca, RiboMed coordinator, and iMM principal researcher, discussed development of gene therapy approaches and presented results from the research group on cardiomyopathies in the seminar “Sarcomeric cardiomyopathies: pathways from bench to bedside”.

Targeting RNA

November 26-27, 2019

On 27th November 2019 Maria-Carmo Fonseca, RiboMed coordinator, and iMM principal researcher, discussed the mRNA biomarkers in response to cancer therapy at the Targeting RNA congress in Frankfurt.

The Targeting RNA congress aimed to bring together leaders in academics and pharma industry to discuss the latest advancements in modulation of RNA.

5e Journée du Réseau d’Imagerie Cellulaire Paris-Saclay

November 14, 2019

Imaging and Signalling was the theme of the 5eJournée du Réseau d’Imagerie Cellulaire Paris-Saclay held on 14thNovember 2019 with the participation of Maria-Carmo Fonseca, RiboMed coordinator, and iMM principal researcher.

SPAOM 2019

November 6-8, 2019

On 6thNovember 2019, Maria-Carmo Fonseca, RiboMed coordinator, and iMM principal researcher, talk about live-cell analysis for pre-mRNA processing at the Spanish & Portuguese Advanced Optical Microscopy (SPAOM) conference in Coimbra, Portugal.

The SPAOM is a joint effort from a Red Española de Microscopía Óptica Avanzada and Portuguese Platform of Biomedical Imaging. The main purpose of SPAOM is to organize an annual congress covering new applications to optical microscopy and image analysis.

Credits: Nuno Moreno
Credits: Nuno Moreno

2019 Brokerslink Conference

October 17-18, 2019

“The longivity challenge and its impact in health insurance” – this theme was aboded by Maria-Carmo Fonseca, RiboMed coordinator, and iMM principal researcher, at 2019 Brokerslink Conference.

The Brokerslink conference, held this year at Bordeaux, France, is an opportunity for our partners and affiliates to meet insurance and risk management experts from across the world.

Credits: Brokenslink Conference
Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops

João C Sabino, Madalena R de Almeida, Patrícia L Abreu, Ana M Ferreira, Paulo Caldas, Marco M Domingues, Nuno C Santos, Claus M Azzalin, Ana Rita Grosso and Sérgio Fernandes de Almeida

eLife 2022

ABSTRACT: DNA oxidation by ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming. The conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) initiates developmental and cell-type-specific transcriptional programs through mechanisms that include changes in the chromatin structure. Here, we show that the presence of 5hmC in the transcribed gene promotes the annealing of the nascent RNA to the template DNA strand, leading to the formation of an R-loop. Depletion of TET enzymes reduced global R-loops in the absence of gene expression changes, whereas CRISPR-mediated tethering of TET to an active gene promoted the formation of R-loops. The genome-wide distribution of 5hmC and R-loops shows a positive correlation in mouse and human stem cells and overlap in half of all active genes. Moreover, R-loop resolution leads to differential expression of a subset of genes that are involved in crucial events during stem cell proliferation. Altogether, our data reveal that epigenetic reprogramming via TET activity promotes co-transcriptional R-loop formation, disclosing new mechanisms of gene expression regulation.

TREX1-dependent DNA damage links nuclear rupture to tumor cell invasion

Edgar R. Gomes and Sérgio F. de Almeida

Development Cell 2021

SUMMARY: Loss of nuclear integrity correlates with increased DNA damage in different tissues. In a recent issue of Cell, Nader et al. reveal that nuclear envelope ruptures in dense tissue microenvironments cause TREX1-dependent DNA damage and promote the transition from in situ to invasive carcinomas.

Live-Cell Imaging of Transcriptional Activity at DNA Double-Strand Breaks

Madalena R. de Almeida, Eduardo Gameiro, Sérgio F. de Almeida and Robert M. Martin

JOVE 2021

ABSTRACT: DNA double-strand breaks (DSB) are the most severe type of DNA damage. Despite the catastrophic consequences on genome integrity, it remains so far elusive how DSBs affect transcription. A reason for this was the lack of suitable tools to simultaneously monitor transcription and the induction of a genic DSB with sufficient temporal and spatial resolution. This work describes a set of new reporters that directly visualize transcription in live cells immediately after the induction of a DSB in the DNA template. Bacteriophage RNA stem-loops are employed to monitor the transcription with single-molecule sensitivity. For targetting the DSB to a specific gene region, the reporter genes are engineered to contain a single recognition sequence of the homing endonuclease I-SceI, otherwise absent from the human genome. A single copy of each reporter gene was integrated into the genome of human cell lines. This experimental system allows the detection of single RNA molecules generated by the canonical gene transcription or by DNA break-induced transcription initiation. These reporters provide an unprecedented opportunity for interpreting the reciprocal interactions between transcription and DNA damage and to disclose hitherto unappreciated aspects of DNA break-induced transcription.

TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells

Bruno Silva, Rajika Arora, Silvia Bione and Claus M. Azzalin

Nature Communications 2021

ABSTRACT: Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required to initiate ALT, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.

The splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing

Evi Goulielmaki, Maria Tsekrekou, Nikos Batsiotos, Mariana Ascensão-Ferreira, Eleftheria Ledaki, Kalliopi Stratigi, Georgia Chatzinikolaou, Pantelis Topalis, Theodore Kosteas, Janine Altmüller, Jeroen A. Demmers, Nuno L. Barbosa-Morais and George A. Garinis

Nature Communications 2021

ABSTRACT: RNA splicing, transcription and the DNA damage response are intriguingly linked in mammals but the underlying mechanisms remain poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the splicing factor XAB2 interacts with the core spliceosome and that it binds to spliceosomal U4 and U6 snRNAs and pre-mRNAs in developing livers. XAB2 depletion leads to aberrant intron retention, R-loop formation and DNA damage in cells. Studies in illudin S-treated cells and Csbm/m developing livers reveal that transcription-blocking DNA lesions trigger the release of XAB2 from all RNA targets tested. Immunoprecipitation studies reveal that XAB2 interacts with ERCC1-XPF and XPG endonucleases outside nucleotide excision repair and that the trimeric protein complex binds RNA:DNA hybrids under conditions that favor the formation of R-loops. Thus, XAB2 functionally links the spliceosomal response to DNA damage with R-loop processing with important ramifications for transcription-coupled DNA repair disorders.

Reduced Lamin A/C Does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Francesco Roncato, Ofer Regev, Sara W. Feigelson, Sandeep Kumar Yadav, Lukasz Kaczmarczyk, Nehora Levi, Diana Drago-Garcia, Samuel Ovadia, Marina Kizner, Yoseph Addadi, João C. Sabino, Yossi Ovadya, Sérgio F. de Almeida, Ester Feldmesser, Gabi Gerlitz and Ronen Alon.

Cancers 2021

ABSTRACT: The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.

Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

João Conde, Ruth A. Pumroy, Charlotte Baker, Tiago Rodrigues, Ana Guerreiro, Bárbara B. Sousa, Marta C. Marques, Bernardo P. de Almeida, Sohyon Lee, Elvira P. Leites, Daniel Picard, Amrita Samanta, Sandra H. Vaz, Florian Sieglitz, Maike Langini, Marc Remke, Rafael Roque, Tobias Weiss, Michael Weller, Yuhang Liu, Seungil Han, Francisco Corzana, Vanessa A. Morais, Cláudia C. Faria, Tânia Carvalho, Panagis Filippakopoulos, Berend Snijder, Nuno L. Barbosa-Morais, Vera Y. Moiseenkova-Bell, and Gonçalo J. L. Bernardes

ACS Central Science 2021

ABSTRACT: The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo. Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.

POINT technology illuminates the processing of polymerase-associated intact nascent transcripts

Rui Sousa-Luís, Gwendal Dujardin, Inna Zukher, Hiroshi Kimura, Carika Weldon, Maria Carmo-Fonseca, Nick J. Proudfoot and Takayuki Nojima

Molecular Cell 2021

ABSTRACT: Mammalian chromatin is the site of both RNA polymerase II (Pol II) transcription and coupled RNA processing. However, molecular details of such co-transcriptional mechanisms remain obscure, partly because of technical limitations in purifying authentic nascent transcripts. We present a new approach to characterize nascent RNA, called polymerase intact nascent transcript (POINT) technology. This three-pronged methodology maps nascent RNA 5′ ends (POINT-5), establishes the kinetics of co-transcriptional splicing patterns (POINT-nano), and profiles whole transcription units (POINT-seq). In particular, we show by depletion of the nuclear exonuclease Xrn2 that this activity acts selectively on cleaved 5′ P-RNA at polyadenylation sites. Furthermore, POINT-nano reveals that co-transcriptional splicing either occurs immediately after splice site transcription or is delayed until Pol II transcribes downstream sequences. Finally, we connect RNA cleavage and splicing with either premature or full-length transcript termination. We anticipate that POINT technology will afford full dissection of the complexity of co-transcriptional RNA processing.

RNA Splicing Defects in Hypertrophic Cardiomyopathy: Implications for Diagnosis and Therapy

Marta Ribeiro, Marta Furtado, Sandra Martins, Teresa Carvalho and Maria Carmo-Fonseca

International Journal of Molecular Sciences 2020

ABSTRACT: Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is predominantly caused by mutations in genes that encode sarcomere-associated proteins. Effective gene-based diagnosis is critical for the accurate clinical management of patients and their family members. However, the introduction of high-throughput DNA sequencing approaches for clinical diagnostics has vastly expanded the number of variants of uncertain significance, leading to many inconclusive results that limit the clinical utility of genetic testing. More recently, developments in RNA analysis have been improving diagnostic outcomes by identifying new variants that interfere with splicing. This review summarizes recent discoveries of RNA mis-splicing in HCM and provides an overview of research that aims to apply the concept of RNA therapeutics to HCM.

Here you can find all the news updates about RiboMed project:

Issue #1 | July 2021 - Click here.
Issue # 2 | December 2021 - Click here.
Issue #3 | July 2022 - Click here.

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