Óscar Fernández-Capetillo Group Leader
T +34 917328000 (Ext 3480)
ofernandez@cnio.es

The Genomic Instability Group centres its research on understanding how cells respond to DNA damage, in particular to a specific type of harm known as replication stress (RS). Oncogene-induced RS has been confirmed as the main source of genomic rearrangements in cancer cells. In mammals, RS triggers a cellular response initiated by ATR and CHK1 kinases, known as the Replicative Stress Response ( RSR ). Throughout the years, our laboratory has developed a wide battery of cellular and animal tools for the study of the RSR. Among them, we have mice with enhanced or limited function of ATR and CHK1 kinases, cell lines in which the RSR can be activated at will and chemical inhibitors of ATR. Our studies have enhanced our understanding of the impact of RS on cancer and ageing, and have provided novel drugs with antitumoural potential that exploit the presence of RS in cancer cells. Overall, our goal is to understand the molecular mechanisms governing genome protection and repair – particularly during replication – and to exploit this knowledge as a way to fight against cancer.

Publications

• Olbrich T, Vega-Sendino M, Murga M, de Carcer G, Malumbres M, Ortega S, Ruiz S, Fernandez-Capetillo O (2019). A Chemical Screen Identifies Compounds Capable of Selecting for Haploidy in Mammalian Cells.. Cell Reports 28, 597-604. Open Access
• Corman A, Jung B, Häggblad M, Bräutigam L, Lafarga V, Lidemalm L, Hühn D, Carreras-Puigvert J, Fernandez-Capetillo O (2019). A Chemical Screen Identifies Compounds Limiting the Toxicity of C9ORF72 Dipeptide Repeats. Cell Chem Biol 26, 235-243.
• Zong D, Adam S, Wang Y, Sasanuma H, Callén E, Murga M, Day A, Kruhlak MJ, Wong N, Munro M, Ray Chaudhuri A, Karim B, Xia B, Takeda S, Johnson N, Durocher D, Nussenzweig A (2019). BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation. Mol Cell 73, 1267-1281.
• Lafarga V, Sung HM, Haneke K, Roessig L, Pauleau AL, Bruer M, Rodriguez-Acebes S, Lopez-Contreras AJ, Gruss OJ, Erhardt S, Mendez J, Fernandez-Capetillo O, Stoecklin G (2019). TIAR marks nuclear G2/M transition granules and restricts CDK1 activity under replication stress. EMBO Rep (in press).
• Baltanás FC, Berciano MT, Tapia O, Narcis JO, Lafarga V, Díaz D, Weruaga E, Santos E, Lafarga M (2019). Nucleolin reorganization and nucleolar stress in purkinje cells of mutant PCD mice. Neurobiol Dis (in press).
• Lafarga V, Sung H-M, Haneke K, Roessig L, Pauleau A-L, Bruer M, Rodríguez-Acebes S, López-Contreras A, Gruss OJ, Erhardt S, Méndez J, Fernández-Capetillo O, Stoecklin G (2019). TIAR controls mitotic entry, maintains genome stability and retains CDK1 in checkpoint bodies.. EMBO Rep 20, pii: e46224.
• Galarreta A, Lecona E, Valledor P, Ubieto P, Lafarga V, Specks J, Fernandez-Capetillo O (2018). USP7 couples DNA replication termination to mitotic entry. bioRxiv (in press).
• Lafarga V, Sirozh O, Diaz-Lopez I, Hisaoka M, Zarzuela E, Boskovic J, Jovanovic B, Fernandez-Leiro R, Munoz J, Stoecklin G, Ventoso I, Fernandez-Capetillo O (2018). DNA and RNA binding mediate the toxicity of arginine-rich peptides encoded by C9ORF72 GGGGCC repeats. bioRxiv (in press).
• Lecona E, Fernandez-Capetillo O (2018). Targeting ATR in cancer. Nat Rev Cancer 18, 586-595.
• Mayor-Ruiz C, Olbrich T, Drosten M, Lecona E, Vega-Sendino M, Ortega S, Dominguez O, Barbacid M, Ruiz S, Fernandez-Capetillo O (2018). ERF deletion rescues RAS deficiency in mouse embryonic stem cells. Genes Dev 32, 568-576.
• Lynch CJ, Bernad R, Calvo I, Nóbrega-Pereira S, Ruiz S, Ibarz N, Martinez-Val A, Graña-Castro O, Gómez-López G, Andrés-León E, Espinosa Angarica V, Del Sol A, Ortega S, Fernandez-Capetillo O, Rojo E, Munoz J, Serrano M (2018). The RNA Polymerase II Factor RPAP1 Is Critical for Mediator-Driven Transcription and Cell Identity. Cell Reports 22, 396-410.
• Lafarga V, Tapia O, Sharma S, Bengoechea R, Stoecklin G, Lafarga M, Berciano MT (2018). CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN. Cell Mol Life Sci 75, 527-576.
• Pacheco S, Maldonado-Linares A, Marcet-Ortega M, Rojas C, Martínez-Marchal M, Fuentes-Lazaro J, Lange J, Jasin M, Keeney S, Fernandez-Capetillo O, Garcia-Caldés M, Roig I (2018). ATR is required to complete meiotic recombination in mice. Nat Commun 9, 2622.
• Mayor-Ruiz C, Dominguez O, Fernandez-Capetillo O (2017). TrapSeq: An RNA Sequencing-Based Pipeline for the Identification of Gene-Trap Insertions in Mammalian Cells.. J Mol Biol 429, 2780-2789.
• Olbrich T, Mayor-Ruiz C, Vega-Sendino M, Gomez C, Ortega S, Ruiz S, Fernandez-Capetillo O. (2017). A p53-dependent response limits the viability of mammalian haploid cells.. Proc Natl Acad Sci USA 114, 9367-9372.
• Lecona E, Rodriguez-Acebes S, Specks J, Lopez-Contreras AJ, Ruppen I, Murga M, Muñoz J, Mendez J, Fernandez-Capetillo O (2016). USP7 is a SUMO deubiquitinase essential for DNA replication.. Nat Struct Mol Biol 23, 270-277.
• Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA, Lee JE, Wong N, Lafarga V, Calvo JA, Panzarino NJ, John S, Day A, Crespo AV, Shen B, Starnes LM, de Ruiter JR, Daniel JA, Konstantinopoulos PA, Cortez D, Cantor SB, Fernandez-Capetillo O, Ge K, Jonkers J, Rottenberg S, Sharan SK, Nussenzweig A (2016). Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535, 382-387.
• Murga M, Lecona E, Kamileri I, Díaz M, Lugli N, Sotiriou SK, Anton ME, Méndez J, Halazonetis TD, Fernandez-Capetillo O (2016). POLD3 Is Haploinsufficient for DNA Replication in Mice.. Mol Cell 63, 877-883.
• Ruiz S, Mayor-Ruiz C, Lafarga V, Murga M, Vega-Sendino M, Ortega S, Fernandez-Capetillo O (2016). A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors.. Mol Cell 62, 307-313.
• Morgado-Palacin I, Day A, Murga M, Lafarga V, Anton ME, Tubbs A, Chen HT, Ergan A, Anderson R, Bhandoola A, Pike KG, Barlaam B, Cadogan E, Wang X, Pierce AJ, Hubbard C, Armstrong SA, Nussenzweig A, Fernandez-Capetillo O (2016). Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.. Sci Signal 9, ra91.
• Nieto-Soler M, Morgado-Palacin I, Lafarga V, Lecona E, Murga M, Callen E, Azorin D, Alonso J, Lopez-Contreras AJ, Nussenzweig A, Fernandez-Capetillo O (2016). Efficacy of ATR inhibitors as single agents in Ewing sarcoma.. Oncotarget 7, 58759-58767.
• Lecona E, Fernandez-Capetillo O (2016). A SUMO and ubiquitin code coordinates protein traffic at replication factories.. Bioessays 38, 1209-1217.
• Fernandez-Capetillo O (2016). The (elusive) role of the SMC5/6 complex.. Cell Cycle 15, 775-776.
• Fernández-Capetillo Ó, Yan N, Dionne J, Bassett D, Sebastian S, Hendon C, Schlichting H, Baker M. (2015). Hopes for the year ahead.. Nature 517, 111-113.
• Alvarez S, Díaz M, Flach J, Rodriguez-Acebes S, López-Contreras AJ, Martínez D, Cañamero M, Fernández-Capetillo O, Isern J, Passegué E, Méndez J (2015). Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality.. Nat Communications 6, 8548.
• Farrés J, Llacuna L, Martin-Caballero J, Martínez C, Lozano JJ, Ampurdanés C, López-Contreras AJ, Florensa L, Navarro J, Ottina E, Dantzer F, Schreiber V, Villunger A, Fernández-Capetillo O, Yélamos J. (2015). PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors.. Cell Death Differ 22, 1144-1157.
• Ruiz S, Fernandez-Capetillo O. (2015). Reducing genomic instability in iPSCs.. Oncotarget 6, 34045-34046.
• Specks J, Lecona E, Lopez-Contreras AJ, Fernandez-Capetillo O (2015). A single conserved residue mediates binding of the ribonucleotide reductase catalytic subunit RRM1 to RRM2 and is essential for mouse development.. Mol Cell Biol 35, 2910-2917.
• Specks J, Nieto-Soler M, Lopez-Contreras AJ, Fernandez-Capetillo O (2015). Modeling the study of DNA damage responses in mice.. Methods Mol Biol 1267, 413-437.
• Lopez-Contreras AJ, Specks J, Barlow JH, Ambrogio C, Desler C, Vikingsson S, Rodrigo-Perez S, Green H, Rasmussen LJ, Murga M, Nussenzweig A, Fernandez-Capetillo O (2015). Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice.. Genes Dev 29, 690-695.
• Ruiz S, Lopez-Contreras AJ, Gabut M, Marion RM, Gutierrez-Martinez P, Bua S, Ramirez O, Olalde I, Rodrigo-Perez S, Li H, Marques-Bonet T, Serrano M, Blasco MA, Batada NN, Fernandez-Capetillo O (2015). Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells.. Nat Communications 6, 8036.
• Jacome A, Gutierrez-Martinez P, Schiavoni F, Tenaglia E, Martinez P, Rodríguez-Acebes S, Lecona E, Murga M, Méndez J, Blasco MA, Fernandez-Capetillo O (2015). NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity.. EMBO J 34, 2604-2619.
• Eguren M, Álvarez-Fernández M, García F, López-Contreras AJ, Fujimitsu K, Yaguchi H, Luque-García JL, Fernández-Capetillo O, Muñoz J, Yamano H, Malumbres M (2014). A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens.. Cell Reports 6, 670-683.
• Ruiz S, Fernandez-Capetillo O (2014). The maternal side of fanconi anemia.. Mol Cell 55, 803-804.
• Winter GE, Radic B, Mayor-Ruiz C, Blomen VA, Trefzer C, Kandasamy RK, Huber KV, Gridling M, Chen D, Klampfl T, Kralovics R, Kubicek S, Fernandez-Capetillo O, Brummelkamp TR, Superti-Furga G (2014). The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.. Nat Chem Biol 10, 768-773.
• Arcas A, Fernández-Capetillo O, Cases I, Rojas AM (2014). Emergence and evolutionary analysis of the human DDR network: implications in comparative genomics and downstream analyses.. Mol Biol Evol 31, 940-961.
• Saiz-Ladera C, Lara MF, Garín M, Ruiz S, Santos M, Lorz C, García-Escudero R, Martínez-Fernández M, Bravo A, Fernández-Capetillo O, Segrelles C, Paramio JM (2014). p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia.. Oncogene 33, 4599-4612.
• Lecona E, Fernández-Capetillo O (2014). Replication stress and cancer: It takes two to tango.. Exp Cell Res 329, 26-34.
• Juan D, Rico D, Marques-Bonet T, Fernández-Capetillo O, Valencia A (2014). Late-replicating CNVs as a source of new genes.. Biol Open 3, pii.231.
• Schulze J, Lopez-Contreras AJ, Uluçkan O, Graña-Castro O, Fernandez-Capetillo O, Wagner EF (2014). Fos-dependent induction of Chk1 protects osteoblasts from replication stress.. Cell Cycle 13, 1980-1986.
• López-Contreras AJ, Ruppen I, Nieto-Soler M, Murga M, Rodriguez- Acebes S, Remeseiro S, Rodrigo-Perez S, Rojas AM, Mendez J, Muñoz J, Fernandez-Capetillo O (2013). A proteomic characterization of factors enriched at nascent DNA molecules.. Cell Reports 3, 1-12.
• Barlow JH, Faryabi RB, Callén E, Wong N, Malhowski A, Chen HT, Gutierrez-Cruz G, Sun HW, McKinnon P, Wright G, Casellas R, Robbiani DF, Staudt L, Fernandez-Capetillo O, Nussenzweig A (2013). Identification of early replicating fragile sites that contribute to genome instability.. Cell 152, 620-632.
• Callen E, Di Virgilio M, Kruhlak MJ, Nieto-Soler M, Wong N, Chen HT, Faryabi RB, Polato F, Santos M, Starnes LM, Wesemann DR, Lee JE, Tubbs A, Sleckman BP, Daniel JA, Ge K, Alt FW, Fernandez-Capetillo O, Nussenzweig MC, Nussenzweig A (2013). 53BP1 Mediates Productive and Mutagenic DNA Repair through Distinct Phosphoprotein Interactions.. Cell 153, 1266-1280.
• Fernandez-Capetillo O, Nussenzweig A (2013). Naked Replication Forks Break apRPArt.. Cell 155, 979-980.
• Marqués-Torrejón MÁ, Porlan E, Banito A, Gómez-Ibarlucea E, Lopez-Contreras AJ, Fernández-Capetillo O, Vidal A, Gil J, Torres J, Fariñas I (2013). Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression.. Cell Stem Cell 12, 88-100.
• Lecona E, Rojas L, Bonasio R, Johnston A, Fernández-Capetillo O, Reinberg D (2013). Polycomb Protein SCML2 Regulates the Cell Cycle by Binding and Modulating CDK/CYCLIN/p21 Complexes.. PLoS Biol 11, e1001737.
• Monasor A, Murga M, Lopez-Contreras AJ, Navas C, Gomez G, Pisano DG, Fernandez-Capetillo O (2013). INK4a/ARF limits the expansion of cells suffering from replication stress.. Cell Cycle 12, 1948-1954.
• Juan D, Rico D, Marques-Bonet T, Fernández-Capetillo O, Valencia A (2013). Late-replicating CNVs as a source of new genes.. Biol Open 2, 1402-1411.