Andres Lopez-Contreras – University of Copenhagen

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CCS > Research > Andres Lopez-Contreras

Andrés López-Contreras

Overview

Chromosome instability leads to genetic alterations that can cause cancer and other diseases. To limit these alterations, cells have evolved complex mechanisms that coordinate cellular responses altogether known as the DNA Damage Response (DDR). However, in many cases the DDR is not sufficient to protect our genomes from either exogenous or endogenous insults such as replication-borne DNA damage. The overall goal of our laboratory is to increase our knowledge of the mechanisms that regulate the DDR and the consequences of their deregulation.  This will help us to dissect and understand the underlying causes of a number of diseases and to identify novel therapeutic strategies. 

With this purpose, we are utilizing a wide range of approaches to investigate chromosomal instability from the underlying molecular mechanisms to its ultimate consequences on health. We are using cellular-based systems to perform screens, gain mechanistic insight and analyse cellular phenotypes in different genetic contexts. In addition, we will generate transgenic mouse models to address the physiological impact of specific genetic alterations and, in particular, their influence on cancer and aging. For both, cellular and mouse models-based studies, we are using the novel CRISPR/Cas9 technology to efficiently manipulate the genome. We also employ high content microscopy (HCM) as a routine approach to quantify alterations in the DDR in our different models. In addition, HCM will allow us to set-up different genetic and drug screenings to identify novel therapeutic targets or compounds with clinical interest. Finally, in collaboration with groups at the Center for Protein Research (CPR), we will perform a number of proteomic studies to investigate novel regulatory networks and the interplay between different proteins involved in the DDR. The most relevant findings will be validated and further characterized using mouse models.

Figure. Overview of the main approaches and methods that we employ to study genomic instability and its regulatory mechanisms.

 

Current projects

Exploring the impact of Replication Stress on Ageing and Cancer
This project is financed from the Danish National Research Program “Sapere Aude – DFF Starting Grant”

Identification of novel targets for the BRCA1 ubiquitin ligase activity.
This project is funded by a KBVU Project from the Danish Cancer Society.

Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability
This project is funded by the European Research Council (ERC-2015-StG)

If you are interested in joining our lab, we want to hear about you and your ideas!
Please, send an e-mail to ajlopez@sund.ku.dk including your CV and a motivation letter.

Recent publications           

  1. Herrtwich L, Nanda I, Evangelou K, Nikolova T, Horn V, Sagar, …, Lopez-Contreras AJ, Grün D, Gorgoulis V, Diefenbach A, Henneke P, Triantafyllopoulou A. DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas. Cell (2016)

  2. 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. Efficacy of ATR inhibitors as single agents in Ewing sarcoma. Oncotarget (2016)

  3. Lecona E, Rodriguez-Acebes S, Specks J, Lopez-Contreras AJ, Ruppen I, Murga M, Muñoz J, Mendez J, Fernandez-Capetillo O. USP7 is a SUMO deubiquitinase essential for DNA replication. Nat Struct Mol Biol (2016)

  4. Figueira I, Fernandes A, Mladenovic Djordjevic A, Lopez-Contreras A, Henriques CM, Selman C, Ferreiro E, Gonos ES, Trejo JL, Misra J, Rasmussen LJ, Xapelli S, Ellam T, Bellantuono I. Interventions for age-related diseases: Shifting the paradigm. Mech Ageing Dev (2016)

Selected publications

  1. 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*. Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. Genes Dev (2015) Apr 1. *Co-corresponding authors.

  2. Specks J, Nieto-Soler M, Lopez-Contreras AJ*, Fernandez-Capetillo O*. Modeling the study of DNA damage responses in mice. Methods Mol Biol (2015). *Co-corresponding authors.

  3. Schulze J*, Lopez-Contreras AJ*, Uluçkan O, Graña-Castro O, Fernandez-Capetillo O, Wagner EF. Fos-dependent induction of Chk1 protects osteoblasts from replication stress. Cell Cycle, 13: 1980-1986 (2014)   * co-first authors

  4. Lopez-Contreras AJ, Ruppen I, Nieto-Soler M, Murga M, Rodriguez-Acebes S, Remeseiro S, Rodrigo-Perez S, Rojas A, Mendez J, Muñoz J, Fernandez-Capetillo O. A proteomic characterization of factors enriched on nascent DNA molecules. Cell Reports, 3: 1105-1116 (2013)

  5. Marques-Torrejon MA, Porlan E, Banito A, Gomez-Ibarlucea E, Lopez-Contreras AJ, Fernandez-Capetillo O, Vidal A, Gil J, Torres J, Fariñas I. Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression. Cell Stem Cell, 12: 88-100 (2013)

  6. Bunting SF, Callen E, Kozak ML, Kim JM, Wong N, Lopez-Contreras AJ, Ludwig T, Baer R, Faryabi RB, Malhowski A, Chen HT, Fernandez-Capetillo O, D'Andrea A, Nussenzweig A. BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell, 46: 125-135 (2012)

  7. Lopez-Contreras AJ, Gutierrez-Martinez P, Specks J, Rodrigo-Perez S, Fernandez-Capetillo O. An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation. J Exp Med, 209:455-461 (2012)

  8. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montaña MF, D'Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol, 18: 1331-1335 (2011)

  9. Lopez-Contreras AJ, Fernandez-Capetillo O. The ATR barrier to replication-born DNA damage. DNA Repair, 9: 1249-55 (2010)

  10. Santos MA, Huen MS, Lopez-Contreras AJ, Klein IA, Jankovic M, Chen H, Wong N, Rodriguez-Barbancho JL, Fernandez-Capetillo O, Nuzzenzweig M, Chen J, Nussenzweig A. RNF8-dependent histone ubiquitinylation contributes to class-switch recombination and meiosis. J Exp Med, 207: 973-81 (2010)