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

The Genomic Instability laboratory centres its research on understanding how cells respond to a specific type of DNA damage known as replication stress (RS), which is the main source of genomic rearrangements in cancer cells. In mammals, RS is sensed and suppressed by a signalling cascade initiated by ATR and CHK1 kinases. Throughout the years, our laboratory has developed a wide battery of cellular and animal tools for the study of RS. These tools include mice with enhanced or limited function of ATR/CHK1 kinases, cell lines in which the RS-response pathway 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 led to novel drugs with antitumour potential that can exploit the presence of RS in cancer cells. Altogether, our main aim is to understand how genome maintenance is safeguarded – particularly during replication – and to exploit this knowledge as a way to fight against cancer.

Publications

• TIAR controls mitotic entry, maintains genome stability and retains CDK1 in checkpoint bodies.(2019)
  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
  EMBO Rep 20, pii: e46224-.
• Targeting ATR in cancer.(2018)
  Lecona E, Fernandez-Capetillo O.
  Nat Rev Cancer 18, 586-595.
• ERF deletion rescues RAS deficiency in mouse embryonic stem cells.(2018)
  Mayor-Ruiz C, Olbrich T, Drosten M, Lecona E, Vega-Sendino M, Ortega S, Dominguez O, Barbacid M, Ruiz S, Fernandez-Capetillo O.
  Genes Dev 32, 568-576.
• The RNA Polymerase II Factor RPAP1 Is Critical for Mediator-Driven Transcription and Cell Identity.(2018)
  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
  Cell Reports 22, 396-410.
• CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.(2018)
  Lafarga V, Tapia O, Sharma S, Bengoechea R, Stoecklin G, Lafarga M, Berciano MT.
  Cell Mol Life Sci 75, 527-576.
• ATR is required to complete meiotic recombination in mice(2018)
  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
  Nat Commun 9, 2622-.
• USP7 couples DNA replication termination to mitotic entry.(2018)
  Galarreta A, Lecona E, Valledor P, Ubieto P, Lafarga V, Specks J, Fernandez-Capetillo O
  bioRxiv (in press).
• DNA and RNA binding mediate the toxicity of arginine-rich peptides encoded by C9ORF72 GGGGCC repeats(2018)
  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
  bioRxiv (in press).
• A Chemical Screen Identifies Compounds Limiting the Toxicity of C9ORF72 Dipeptide Repeats.(2018)
  Corman A, Jung B, Häggblad M, Bräutigam L, Lafarga V, Lidemalm L, Hühn D, Carreras-Puigvert J, Fernandez-Capetillo O.
  Cell Chem Biol (in press).
• TrapSeq: An RNA Sequencing-Based Pipeline for the Identification of Gene-Trap Insertions in Mammalian Cells.(2017)
  Mayor-Ruiz C, Dominguez O, Fernandez-Capetillo O
  J Mol Biol 429, 2780-2789.
• A p53-dependent response limits the viability of mammalian haploid cells.(2017)
  Olbrich T, Mayor-Ruiz C, Vega-Sendino M, Gomez C, Ortega S, Ruiz S, Fernandez-Capetillo O.
  Proc Natl Acad Sci USA 114, 9367-9372.
• USP7 is a SUMO deubiquitinase essential for DNA replication.(2016)
  Lecona E, Rodriguez-Acebes S, Specks J, Lopez-Contreras AJ, Ruppen I, Murga M, Muñoz J, Mendez J, Fernandez-Capetillo O
  Nat Struct Mol Biol 23, 270-277.
• Replication fork stability confers chemoresistance in BRCA-deficient cells(2016)
  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
  Nature 535, 382-387.
• POLD3 Is Haploinsufficient for DNA Replication in Mice.(2016)
  Murga M, Lecona E, Kamileri I, Díaz M, Lugli N, Sotiriou SK, Anton ME, Méndez J, Halazonetis TD, Fernandez-Capetillo O
  Mol Cell 63, 877-883.
• A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors.(2016)
  Ruiz S, Mayor-Ruiz C, Lafarga V, Murga M, Vega-Sendino M, Ortega S, Fernandez-Capetillo O
  Mol Cell 62, 307-313.
• Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.(2016)
  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
  Sci Signal 9, ra91-.
• Efficacy of ATR inhibitors as single agents in Ewing sarcoma.(2016)
  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
  Oncotarget 7, 58759-58767.
• A SUMO and ubiquitin code coordinates protein traffic at replication factories.(2016)
  Lecona E, Fernandez-Capetillo O
  Bioessays 38, 1209-1217.
• The (elusive) role of the SMC5/6 complex.(2016)
  Fernandez-Capetillo O
  Cell Cycle 15, 775-776.
• Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells.(2015)
  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
  Nat Communications 6, 8036-.
• NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity.(2015)
  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
  EMBO J 34, 2604-2619.
• Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice.(2015)
  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
  Genes Dev 29, 690-695.
• Hopes for the year ahead.(2015)
  Fernández-Capetillo Ó, Yan N, Dionne J, Bassett D, Sebastian S, Hendon C, Schlichting H, Baker M.
  Nature 517, 111-113.
• Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality.(2015)
  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
  Nat Communications 6, 8548-.
• PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors.(2015)
  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.
  Cell Death Differ 22, 1144-1157.
• Reducing genomic instability in iPSCs.(2015)
  Ruiz S, Fernandez-Capetillo O.
  Oncotarget 6, 34045-34046.
• A single conserved residue mediates binding of the ribonucleotide reductase catalytic subunit RRM1 to RRM2 and is essential for mouse development.(2015)
  Specks J, Lecona E, Lopez-Contreras AJ, Fernandez-Capetillo O
  Mol Cell Biol 35, 2910-2917.
• Modeling the study of DNA damage responses in mice.(2015)
  Specks J, Nieto-Soler M, Lopez-Contreras AJ, Fernandez-Capetillo O
  Methods Mol Biol 1267, 413-437.
• A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens.(2014)
  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
  Cell Reports 6, 670-683.
• Fos-dependent induction of Chk1 protects osteoblasts from replication stress.(2014)
  Schulze J, Lopez-Contreras AJ, Uluçkan O, Graña-Castro O, Fernandez-Capetillo O, Wagner EF
  Cell Cycle 13, 1980-1986.
• The maternal side of fanconi anemia.(2014)
  Ruiz S, Fernandez-Capetillo O
  Mol Cell 55, 803-804.
• The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.(2014)
  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
  Nat Chem Biol 10, 768-773.
• Emergence and evolutionary analysis of the human DDR network: implications in comparative genomics and downstream analyses.(2014)
  Arcas A, Fernández-Capetillo O, Cases I, Rojas AM
  Mol Biol Evol 31, 940-961.
• p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia.(2014)
  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
  Oncogene 33, 4599-4612.
• Replication stress and cancer: It takes two to tango.(2014)
  Lecona E, Fernández-Capetillo O
  Exp Cell Res 329, 26-34.
• Late-replicating CNVs as a source of new genes.(2014)
  Juan D, Rico D, Marques-Bonet T, Fernández-Capetillo O, Valencia A
  Biol Open 3, pii.231-.
• A proteomic characterization of factors enriched at nascent DNA molecules.(2013)
  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
  Cell Reports 3, 1-12.
• Identification of early replicating fragile sites that contribute to genome instability.(2013)
  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
  Cell 152, 620-632.
• 53BP1 Mediates Productive and Mutagenic DNA Repair through Distinct Phosphoprotein Interactions.(2013)
  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
  Cell 153, 1266-1280.
• Naked Replication Forks Break apRPArt.(2013)
  Fernandez-Capetillo O, Nussenzweig A
  Cell 155, 979-980.
• Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression.(2013)
  Marqués-Torrejón MÁ, Porlan E, Banito A, Gómez-Ibarlucea E, Lopez-Contreras AJ, Fernández-Capetillo O, Vidal A, Gil J, Torres J, Fariñas I
  Cell Stem Cell 12, 88-100.
• Polycomb Protein SCML2 Regulates the Cell Cycle by Binding and Modulating CDK/CYCLIN/p21 Complexes.(2013)
  Lecona E, Rojas L, Bonasio R, Johnston A, Fernández-Capetillo O, Reinberg D
  PLoS Biol 11, e1001737-.
• INK4a/ARF limits the expansion of cells suffering from replication stress.(2013)
  Monasor A, Murga M, Lopez-Contreras AJ, Navas C, Gomez G, Pisano DG, Fernandez-Capetillo O
  Cell Cycle 12, 1948-1954.
• Late-replicating CNVs as a source of new genes.(2013)
  Juan D, Rico D, Marques-Bonet T, Fernández-Capetillo O, Valencia A
  Biol Open 2, 1402-1411.