Grupo de Inestabilidad Genómica

Óscar Fernández-Capetillo Jefe de Grupo
T +34 917328000 (Ext 3480)
ofernandez@cnio.es

Investigadores Científicos

Vanesa Lafarga
Matilde Murga

Becarios Post-doctorales

Ivó Hernández

Becarios Pre-Doctorales

Gema López
Jorge Mota
Belén Navarro
Anabel Sáez

Técnicos de Laboratorio

Marta Elena Antón
Alicia González
Mario López
Sara Rodrigo

The Genomic Instability Group focuses its research on understanding the molecular mechanisms leading to cancer and other age-related diseases, with the ultimate goal of translating this knowledge into novel therapeutic strategies. Our initial investigations centred on Replicative Stress (RS), a type of DNA damage sensed by the ATR kinase, and that is particularly abundant in some cancer cells. Our work in this area led to the discovery of selective ATR inhibitors that were further improved to enable their clinical development as anticancer agents. Next, we became increasingly interested in understanding the mechanisms of drug resistance to specific agents, such as inhibitors of ATR or USP7. More recently, our group has revealed that one of the most frequent mutations in human cancer, inactivation of the tumour suppressor FBXW7, leads to multidrug resistance (MDR). Importantly, we have also discovered strategies to overcome MDR, which is an important area of our current research.

Publicaciones

Kanellis DC, Zisi A, Skrott Z, Lemmens B, Espinoza JA, Kosar M, Björkman A, Li X, Arampatzis S, Bartkova J, Andújar-Sánchez M, Fernandez-Capetillo O, Mistrik M, Lindström MS, Bartek J. (2023). Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET. Cell Death Differ 30, 1666-1678. Publicación CNIO.
Sayago C, Sánchez-Wandelmer J, García F, Hurtado B, Lafarga V, Prieto P, Zarzuela E, Ximénez-Embún P, Ortega S, Megías D, Fernández-Capetillo O, Malumbres M, Munoz J. (2023). Decoding protein methylation function with thermal stability analysis.. Nat Commun 14, 3016. Publicación CNIO.
Schlegel J, Porebski B, Andronico L, Hanke L, Edwards S, Brismar H, Murrell B, McInerney GM, Fernandez-Capetillo O, Sezgin E. (2023). A Multiparametric and High-Throughput Platform for Host-Virus Binding Screens. Nano Lett (in press). Publicación CNIO.
Fueyo-Marcos E, Lopez-Pernas G, Fustero-Torre C, Antón ME, Al-Shahrour F, Fernández-Capetillo O, Murga M. (2023). PD-L1ATTAC mice reveal the potential of depleting PD-L1 expressing cells in cancer therapy. Aging (Albany NY) 15, 1791-1807. Publicación CNIO.
Barz M, Porebski B, Panshikar P, Häggbladd M, Hühn D, Fernandez-Capetillo O. (2023). A chemical screen underscores the essential role of STAT1-dependent IFN? signaling to regulate HLA-I expression in cancer cells. MicroPubl Biol (in press). Publicación CNIO.
Galindo-Campos MA, Lutfi N, Bonnin S, Martínez C, Velasco-Hernandez T, García-Hernández V, Martin-Caballero J, Ampurdanés C, Gimeno R, Colomo L, Roue G, Guilbaud G, Dantzer F, Navarro P, Murga M, Fernandez-Capetillo O, Bigas A, Menendez P, Sale J, Yélamos J (2022). Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice.. Blood 139, 228-239. Publicación CNIO.
Hanke L, Das H, Sheward DJ, Perez Vidakovics L, Urgard E, Moliner-Morro A, Kim C, Karl V, Pankow A, Smith NL, Porebski B, Fernandez-Capetillo O, Sezgin E, Pedersen GK, Coquet JM, Hällberg BM, Murrell B, McInerney GM (2022). A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo. Nat Commun 13, 155. Publicación CNIO. Open Access
Corman A, Sirozh O, Lafarga V, Fernandez-Capetillo O. (2022). Targeting the nucleolus as a therapeutic strategy in human disease. Trends Biochem Sci (in press). Publicación CNIO.
Sanchez-Burgos L, Navarro-González B, García-Martín S, Sirozh O, Mota-Pino J, Fueyo-Marcos E, Tejero H, Antón ME, Murga M, Al-Shahrour F, Fernandez-Capetillo O (2022). Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells. EMBO Mol Med 0, e15855. Publicación CNIO.
Hühn D, Martí-Rodrigo P, Mouron S, Hansel C, Tschapalda K, Porebski B, Häggblad M, Lidemalm L, Quintela-Fandino M, Carreras-Puigvert J, Fernandez-Capetillo O. (2022). Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells. Mol Oncol 16, 148-165. Publicación CNIO. Open Access
Murga M, Fernandez-Capetillo O (2022). Emerging concepts in drug discovery for cancer therapy. Mol Oncol 16, 3757-3760. Publicación CNIO.
Egea J, López-Muñoz F, Fernández-Capetillo O, Reiter RJ, Romero A (2022). Alkylating Agent-Induced Toxicity and Melatonin-Based Therapies. Front Pharmacol 13, 873197. Publicación CNIO.
Sanchez-Burgos L, Gómez-López G, Al-Shahrour F, Fernandez-Capetillo O (2022). An in silico analysis identifies drugs potentially modulating the cytokine storm triggered by SARS-CoV-2 infection.. Sci Rep 12, 1626. Publicación CNIO. Open Access
Colicchia V, Häggblad M, Sirozh O, Porebski B, Balan M, Li X, Lidemalm L, Carreras-Puigvert J, Hühn D, Fernandez-Capetillo O (2022). New regulators of the tetracycline-inducible gene expression system identified by chemical and genetic screens. FEBS Open Bio 12, 1896-1908. Publicación CNIO.
Galarreta A, Valledor P, Ubieto-Capella P, Lafarga V, Zarzuela E, Muñoz J, Malumbres M, Lecona E, Fernandez-Capetillo O (2021). USP7 limits CDK1 activity throughout the cell cycle. EMBO J 40, e99692. Publicación CNIO.
Lafarga V, Sirozh O, Díaz-López I, Galarreta A, Hisaoka M, Zarzuela E, Boskovic J, Jovanovic B, Fernandez-Leiro R, Muñoz J, Stoecklin G, Ventoso I, Fernandez-Capetillo O (2021). Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides. EMBO J 40, e99692. Publicación CNIO.
Franz A, Valledor P, Ubieto-Capella P, Pilger D, Galarreta A, Lafarga V, Fernández-Llorente A, de la Vega-Barranco G, den Brave F, Hoppe T, Fernandez-Capetillo O, Lecona E (2021). USP7 and VCP FAF1 define the SUMO/Ubiquitin landscape at the DNA replication fork. Cell Reports 37, 109819. Publicación CNIO.
Corman A, Kanellis DC, Michalska P, Häggblad M, Lafarga V, Bartek J, Carreras-Puigvert J, Fernandez-Capetillo O (2021). A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors. PLoS Biol 19, e3001263. Publicación CNIO.
Galarreta A, Valledor P, Fernandez-Capetillo O, Lecona E. (2021). Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1.. Int J Mol Sci 22, 8796. Publicación CNIO.
Atashpaz S, Samadi Shams S, Gonzalez JM, Sebestyén E, Arghavanifard N, Gnocchi A, Albers E, Minardi S, Faga G, Soffientini P, Allievi E, Cancila V, Bachi A, Fernández-Capetillo Ó, Tripodo C, Ferrari F, López-Contreras AJ, Costanzo V (2020). ATR expands embryonic stem cell fate potential in response to replication stress. Elife 12, e54756. Publicación CNIO. Open Access
Reglero C, Lafarga V, Rivas V, Albitre Á, Ramos P, Berciano SR, Tapia O, Martínez-Chantar ML, Mayor F Jr, Penela P (2020). GRK2-Dependent HuR Phosphorylation Regulates HIF1a Activation Under Hypoxia or Adrenergic Stress. Cancers 12, E1216. Publicación CNIO. Open Access
Albers E, Avram A, Sbroggio M, Fernandez-Capetillo O, Lopez-Contreras AJ (2020). Supraphysiological protection from replication stress does not extend mammalian lifespan.. Aging (Albany NY) 12, 5612-5624. Publicación CNIO.
Berciano MT, Castillo-Iglesias MS, Val-Bernal JF, Lafarga V, Rodriguez-Rey JC, Lafarga M, Tapia O (2020). Mislocalization of SMN from the I-band and M-band in human skeletal myofibers in spinal muscular atrophy associates with primary structural alterations of the sarcomere.. Cell Tissue Res 381, 461-478. Publicación CNIO.
Morales C, Ruiz-Torres M, Rodríguez-Acebes S, Lafarga V, Rodríguez-Corsino M, Megías D, Cisneros DA, Peters JM, Méndez J, Losada A (2020). PDS5 proteins are required for proper cohesin dynamics and participate in replication fork protection. J Biol Chem 295, 146-157. Publicación CNIO. Open Access
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. Publicación CNIO.
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. Publicación CNIO.
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. Publicación CNIO. 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. Publicación CNIO.
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 20, e46224. Publicación CNIO.
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 127, 312-322. Publicación CNIO.
Lecona E, Fernandez-Capetillo O (2018). Targeting ATR in cancer. Nat Rev Cancer 18, 586-595. Publicación CNIO.
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. Publicación CNIO. Open Access
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. Publicación CNIO. Open Access
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. Publicación CNIO.
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. Publicación CNIO. Open Access
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). Publicación CNIO.
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). Publicación CNIO.