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Fernandez-Capetillo O.,Genomic Instability Group
EMBO Reports | Year: 2010

Ageing is an unavoidable corollary to being alive; the most intuitive interpretation of ageing being that it is the consequence of progressive body degeneration. In agreement with this, current models propose that ageing occurs through a stepwise accumulation of DNA damage, which ultimately limits the regenerative capacity of tissues. On the other hand, there is increasing evidence that fetal distress can influence the development of disease in adult life, a phenomenon known as intrauterine programming. The extent to which an intrauterine exposure to DNA damage can compromise lifespan remains unclear. My group has recently generated a murine model of a human syndrome linked to defective DNA repair and observed that these animals age prematurely, but the accumulation of DNA damage is restricted mostly to the embryonic period. Here, I discuss the implications of this finding and propose that ageing can be influenced by fetal distress. © 2010 European Molecular Biology Organization. Source

Lecona E.,Genomic Instability Group
Nature Structural and Molecular Biology | Year: 2016

Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced away from replisomes. Our findings provide a model explaining the differential accumulation of SUMO and Ub at replication forks and identify an essential role of USP7 in DNA replication that should be considered in the development of USP7 inhibitors as anticancer agents. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source

SUMO protein with the areas marked with ubiquitin in green. Credit: CNIO Three years ago, the research team directed by Óscar Fernández-Capetillo, head of the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO), obtained, for the first time, a panoramic view of the proteins that intervene in one of the most important and delicate cellular processes: the copying of genetic material during cellular division. They observed that the parts of the genome where the DNA was copied were also very rich in the modification by some very particular proteins, SUMOylations, and poor in others, ubiquitinations, but they were unable to understand why. The continuation of the paper, published today in the Nature Structural & Molecular Biology journal, reveals how the balance between these chemical markers in these regions is, in fact, key for the division of genetic material. During this process, the USP7 protein travels with an entourage of molecules that form part of the replisome—a set of proteins involved in copying the DNA—and eliminates the ubiquitination marks of proteins in the complex, thus explaining the low concentration of ubiquitin in these areas. "USP7 acts as an traffic officer that regulates the marks or traffic signs near the replisome. Eliminating ubiquitin prevents the proteins at the replisome from being expelled, thus favouring their concentration and the DNA copying process," explains Fernández-Capetillo. As the team described in the previous paper, replisomes contain up to 50 different proteins that participate in the delicate process of copying genetic material. Some proteins open DNA's double helix, others twist it to favour copying, others stabilise it, etc. They all move together through the genome to ensure a complete copy. In order to understand the role of USP7 and its cutting action on ubiquitin marks during the DNA copying process, the researchers used advanced protein tools. "We knew that replisome proteins could present both modifications simultaneously [ubiquitinations and SUMOylations], but we did not know how they worked," explains Fernández-Capetillo. "We now know that USP7 eliminates the ubiquitin marks on proteins that are also SUMOylated in replication areas, which explains why there is a low concentration of ubiquitin and high levels of SUMO." This balance between SUMO and ubiquitin establishes a code that regulates the concentration of proteins in the replisome. "If a protein is SUMOylated, it becomes enriched in the replisome, but if it is also ubiquitinated, it is expelled. This is a code of signals or flags that regulates the concentration of factors in the DNA replication area," say the researchers. Apart from being of academic interest, these studies are relevant for chemotherapy. USP7 inhibitors are currently being studied as possible anti-cancer agents in pre-clinical tests. "The model that had been proposed is that the compounds increase p53 levels, resulting in the suicide of tumour cells. Our data indicate that USP7 is essential for genome replication in cells with or without p53." With these data, the authors of the paper warn that these molecules may not be specifically anti-tumour agents. "We believe they inhibit the cell division process regardless of whether the cells are cancerous or healthy and, therefore, their use for treating cancer in the future will have to be reconsidered." Explore further: Researchers 'capture' the replication of the human genome for the first time More information: Emilio Lecona et al. USP7 is a SUMO deubiquitinase essential for DNA replication, Nature Structural & Molecular Biology (2016). DOI: 10.1038/nsmb.3185

Blasco M.A.,Telomeres and Telomerase Group | Serrano M.,Tumor Suppression Group | Fernandez-Capetillo O.,Genomic Instability Group
EMBO Journal | Year: 2011

The discovery of a simple protocol capable of generating pluripotent stem cells from terminally differentiated cells has been one of the most promising breakthroughs in recent biomedical research. Since their discovery, manuscripts characterizing properties of induced Pluripotent Stem (iPS) have flooded the literature. Among others, the analysis of the transcriptome and epigenome of iPS is now a recurrent theme that is helping to understand the molecular mechanisms behind reprogramming. Recent works have revealed that transcriptional and epigenetic reprogramming is often incomplete, which has raised some concerns on the nature of iPS. Inevitably, now the genome itself of iPS has been scrutinized; and the reports come with an unexpected twist: the presence of mutations in the genome of iPS. © 2011 European Molecular Biology Organization | All Rights Reserved. Source

Lopez-Contreras A.J.,Genomic Instability Group | Fernandez-Capetillo O.,Genomic Instability Group
DNA Repair | Year: 2010

Replication comes with a price. The molecular gymnastics that occur on DNA during its duplication frequently derive to a wide spectrum of abnormalities which are still far from understood. These are brought together under the unifying term " replicative stress" (RS) which likely stands for large and unprotected regions of single-stranded DNA (ssDNA). In addition to RS, recombinogenic stretches of ssDNA are also formed at resected DNA double strand breaks (DSBs). Both situations converge on a ssDNA intermediate, which is the triggering signal for a damage situation. The cellular response in both cases is coordinated by a phosphorylation-based signaling cascade that starts with the activation of the ATR (ATM and Rad3-related) kinase. Given that ATR is essential for replicating cells, understanding the consequences of a defective ATR response for a mammalian organism has been limited until recent years. We here discuss on the topic and review the findings that connect ATR to ageing and cancer. © 2010 Elsevier B.V. Source

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