Un equipo del CABIMER (centro mixto CSIC-US-UPO-Junta de Andalucía), ha identificado factores que amenazan la supervivencia de las células en ausencia de mecanismos de vigilancia del ciclo celular, como en el caso de los tumores. La investigación ha revelado la capacidad de la proteína humana PrimPol, cuando es expresada en levaduras como organismos modelo, de prevenir la degradación masiva del ADN que ocurre cuando fallan estos mecanismos de vigilancia, un proceso denominado checkpoint. Los resultados sugieren un posible papel para esta proteína en la supervivencia de las células tumorales, ya que estas acumulan mutaciones en el checkpoint que les permiten ser resistentes a tratamientos como la quimioterapia.

El material genético (ADN) ha de replicarse de manera eficiente y fidedigna en cada división celular. Este proceso es el periodo más vulnerable del ciclo celular, por tanto, es esencial identificar los factores que pueden alterarlo. Uno de los principales mecanismos de vigilancia del ciclo celular es el punto de control o checkpoint de replicación, conservado por la evolución desde levaduras hasta humanos. Este punto de vigilancia supervisa la correcta replicación del ADN y, en caso de daño, coordina los sistemas de reparación, parando el ciclo celular. Cuando falla, la célula se vuelve especialmente vulnerable al daño en el ADN, lo que conlleva consecuencias letales irreversibles.

Publicado en la revista Nucleic Acids Research, el trabajo, cuyo primer autor es Iván Núñez Martín, identifica además tres factores específicos (Rad51, Mus81 y Rad5) como responsables de esta toxicidad, utilizando la levadura como organismo modelo. Aunque normalmente ayudan a la progresión de la replicación, estos mismos factores son responsables de la degradación masiva del ADN recién sintetizado en células que carecen del sistema de vigilancia, como ocurre en la mayoría de las células cancerígenas.

Iván Núñez Martín, primer autor del trabajo, junto a Belén Gómez González, investigadora de la Universidad de Sevilla que ha liderado el proyecto

“Dado que las células cancerosas acumulan mutaciones en el checkpoint que les permiten tolerar la proliferación celular descontrolada, estos hallazgos sugieren que la adquisición de mutaciones adicionales en factores como los identificados en este trabajo podrían ser responsables de quimioresistencia al promover la supervivencia al daño”, indica Belén Gómez González, investigadora de la Universidad de Sevilla (US) que ha liderado el proyecto.

Esta investigación se ha realizado en el grupo de Inestabilidad Genética y Cáncer del investigador Andrés Aguilera en CABIMER, en colaboración con John Diffley, del Instituto Francis Crick de Londres (Reino Unido), y Luis Blanco, del Centro de Biología Molecular Severo Ochoa (CBM-CSIC-UAM).

Referencia

Iván Núñez-Martín, Lucy S Drury, María I Martínez-Jiménez, Luis Blanco, John F X Diffley, Andrés Aguilera, Belén Gómez-González, S-phase checkpoint protects from aberrant replication fork processing and degradation, Nucleic Acids Research, DOI: 10.1093/nar/gkaf707

Contacto

CBM-CSIC-UAM Comunicación – comunicacion@csic.es

La entrada Revelan factores potencialmente clave en la resistencia al daño de las células cancerosas se publicó primero en Centro de Biología Molecular Severo Ochoa.

The governments of Spain and Catalonia join forces to upgrade the ALBA Synchrotron facilities. This institutional agreement, which guarantees the necessary resources, was announced yesterday. This is also excellent news for ICN2, as it shares numerous projects and research lines with ALBA.

Researchers discover how the interaction of two “epigenetic guardians” protects neuronal identity

• This study shows that the enzymes KDM1A and KDM5C collaborate to prevent neurons from activating inappropriate genes, ensuring their proper function.
• The findings, published in Cell Reports, open new avenues to understand the origin of neurological disorders associated with mutations in these genes, such as intellectual disability.

Photo: Sergio Niñerola, Ángel Barco, Juan Paraíso Luna, and Beatriz del Blanco, IN CSIC-UMH researchers

Neurons are highly specialized cells, and their proper functioning depends on preserving their identity throughout life. The team from the Transcriptional and Epigenetic Mechanisms of Neuronal Plasticity laboratory, led by Ángel Barco at the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) of Elche, has identified that two enzymes, KDM1A and KDM5C, interact to act as true “epigenetic guardians”. Their role is to silence genes that do not belong to neurons and to keep only the appropriate instructions active.

To carry out this study, recently published in Cell Reports, the team used a mouse model in which they simultaneously deleted the KDM1A and KDM5C genes in neurons of the adult brain. This allowed them to investigate what happens when this epigenetic control is lost in mature neurons, and not only during development. “What is surprising is that the joint action of these two enzymes goes beyond the sum of their individual effects”, says Barco, explaining: “When both fail, the neurons begin to express genes that do not belong to it, with negative consequences for memory, learning ability, and the animal’s regulation of anxiety”.

Through a multidisciplinary approach combining genetics, molecular biology, electrophysiology, super-resolution microscopy, behavioral studies, and large-scale genomic analyses, the researchers observed that the loss of both enzymes profoundly alters the neuron’s epigenetic landscape: several genomic regions accumulated an epigenetic mark (H3K4me3), usually associated with active genes, in areas that should remain inactive. They also detected a disorganization in the three-dimensional structure of the neuronal genome. These changes result in alterations in neuronal physiology, such as increased excitability, which negatively impact the behavior and cognitive abilities of the mice.

Images of the nucleus of an excitatory neuron of a control mouse (left) and a mouse in which KDM1A and KDM5C have been simultaneously deleted in the adult brain. The DAPI signal (DNA) is shown in gray, and the H3K27me3 signal, an epigenetic mark associated with repression, is shown in color. Source: Cell Reports.

These results represent progress in understanding the origin of neurological disorders associated with intellectual disability caused by mutations in epigenetic regulators: “Understanding how these enzymes interact not only helps us decipher the biology of neurons, but also to identify possible mechanisms involved in neurological diseases”, highlights Juan Paraíso Luna, co-first author of the article.

This study complements previous work from the same laboratory that had already demonstrated the relevance of each of these enzymes individually: KDM1A, essential to preserve the three-dimensional organization of the genome and prevent its deterioration associated with aging, and KDM5C, necessary to avoid erroneous transcriptions and to fine-tune neuronal responses to stimuli. The novelty now is that both proteins work together to maintain neuronal identity. “Mutations in the Kdm1a and Kdm5c genes have been associated in humans with intellectual disability and other neurological disorders, so this work opens the door to new research that can help us delve deeper into the origin of certain brain diseases”, concludes Barco.

“Cooperative control of neuron-specific repressive chromatin states by intellectual-disability-linked KDM1A and KDM5C demethylases.” Martín-González AM, Paraíso-Luna J, Niñerola S, Del Blanco B, Robles RM, Herrera ML, Muñoz-Viana R, Geijo-Barrientos E and Barco A. Cell Reports. 2025 44, 116201. DOI https://doi.org/10.1016/j.celrep.2025.116201

This work was made possible thanks to collaboration with the group of Professor Emilio Geijo, from the UMH Department of Physiology, and funding from La Marató de TV3, the Spanish State Research Agency, the Generalitat Valenciana, and the “LaCaixa” Foundation.

Source: Institute for Neurosciences CSIC-UMH (in.comunicacion@umh.es)

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The ICIQ Summer Fellowship Programme 2025 has been successfully concluded, offering a hands-on learning experience to eleven students. This unique opportunity, granted by ICIQ through the Severo Ochoa Excellence programme, provided the participants to immerse themselves in research projects, gaining insights and practical skills in chemistry and related fields.

Throughout the programme, the students were mentored by a PhD student or a senior researcher under the supervision and guidance of an ICIQ Group Leader, enabling them to apply theoretical knowledge to practical scenarios. This hands-on approach allowed participants to deepen their understanding of the subject matter while enhancing their problem-solving abilities in a research environment.

This week, during the closing ceremony of the Summer Fellows 2025 programme, all participants presented the research projects they have been working on during these two months of training. It was a working session that served as a shining example of emerging talent and research.

Reflecting on the programme’s success, Prof. Antonio M. Echavarren, ICIQ Group Leader and Scientific Director of the Severo Ochoa Programme at the Institute, stated, “throughout the programme, the students have displayed remarkable curiosity, commitment, and a genuine passion for science. Their performance not only reflects their potential but also inspires optimism for the future of research in chemistry.”

The closing ceremony took place yesterday, September 9^th, and was chaired by Prof. Beatriz Prieto-Simón, Group Leader at ICIQ, and Dana Loughran, ICIQ Talent Officer.

These fellowships are funded by ICIQ with the support of the “Severo Ochoa Centres of Excellence Program (CEX2024-001469-S funded by MICIU/AEI/10.13039/501100011033)

La entrada Rising talent and research shine in the ICIQ Summer Fellowship Programme se publicó primero en ICIQ.