aDDRess

The Institute of Molecular Biology and Biotechnology (IMBB), is one of the 7 Institutes of the Foundation for Research and Technology (FORTH) and the most prominent research institution in Greece, with an outstanding track record of excellence. IMBB is located on the island of Crete, an EU convergence region. IMBB is an internationally known and highly competitive research institute, with a modern infrastructure and a broad range of research, development and educational activities. IMBB concentrates its research efforts using model systems suitable to provide answers to specific biological questions in which the field of DNA repair, DNA damage and cancer is central. Key facilities involve state-of-the-art mouse facilities, (in vivo) imaging facilities, “omics” and bioinformatics facilities.

The Erasmus Medical Center (Erasmus MC) is the largest Academic Medical Center of the Netherlands. In 2010 the medical educational program was elected to be the best of the country. In terms of scientific impact in clinical research, an independent international bibliometric analysis has ranked the Erasmus Medical Center as the first medical institution in Europe, and globally at position 20. The Dept. of Genetics of the Erasmus MC has a globally leading position in the field of genome (in)stability and DNA repair. All molecular, cell biological, genetic (e.g. mouse transgenics), biochemical, high throughput ‘omics’, bioinformatics expertise and facilities are available, permitting efficient, multi-disciplinary front-line research.

The Vermeulen laboratory is mainly focussed on Nucleotide Excision Repair (NER) and its connection to transcription and chromatin modifications. The research covers NER analysis at the molecular and cellular level, extending to mouse-models and human syndromes. The laboratory hosts a large laboratory tool-kit for NER, including cloned genes, purified proteins, antibodies, defined NER-deficient cell lines and mouse-models as well as a variety of dedicated DNA repair assays. The lab has developed sophisticated microscopic and spectroscopic procedures to quantitatively measure protein dynamics and reaction kinetics of chromatin-associated processes using GFP-tagged repair /transcription and chromatin remodelling factors. Next to live cell imaging the lab uses C.elegans and mouse-models to dissect genetic networks and to study the consequences of compromised NER. Recent genetic screens and proteomic studies have identified different chromatin remodelling factors which are implicated in various stages of the UV-induced DNA damage response. In addition, the lab currently studies the role of different Histone-chaperones in processing NER. Finally, within a dedicated proteomic analysis to reveal the UV-induced ubiquitinome several new NER-modulating factors have been identified, their exact molecular action within DDR will be further investigated using the laboratory NER tool-kit.

In dividing cells, faithful duplication of the genome must be accompanied by reproduction of the chromatin landscape on new DNA. Our research focuses on how human cells replicate chromatin and ensure transmission of genetic and epigenetic information during cell division.

Assembly of new DNA into chromatin requires efficient provision of new histones along with recycling of old ones that carry information in post-translational modifications. We study how histone chaperones ensure this process. To dissect how specific chromatin structures are restored, we do proteomic profiling of newly synthesized chromatin. This, together with RNAi screening, allows us to identify and functionally characterize new factors important for maintenance of genome integrity and chromatin states. We are also interested in how perturbation of DNA replication impinges on chromatin maintenance, since repair operations that rescue damaged replication forks can challenge chromatin restoration. Replication stress is frequent in cancer cells, and we are pursuing the idea that replication stress could be a source of epigenetic variation that contributes to tumour heterogeneity.

Selected publications:

• Alabert, C., and Groth, A. (2012). Chromatin replication and epigenome maintenance. Nature reviews Molecular cell biology 13, 153-167.
• Ask, K., Jasencakova, Z., Menard, P., Feng, Y., Almouzni, G., and Groth, A. (2012). Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply. The EMBO journal 31, 2013-2023.
• Jasencakova Z, Scharf AN, Ask K, Corpet A, Imhof A, Almouzni G, Groth A. (2010) Replication stress interferes with histone recycling and predeposition marking of new histones. Mol Cell 37: 736-743
• Jasencakova Z, Groth A. (2010) Replication stress, a source of epigenetic aberrations in cancer? BioEssays 32: 847-855

The recently established Cologne Excellence Cluster on Cellular Stress Responses in Ageing-associated Diseases (CECAD) brings together researchers and clinicians at the University of Cologne and the new Max Planck Institute for Biology of Ageing in a unique research venture to advance ageing research. CECAD is the first ever European research centre to dedicate itself solely to discovering the underlying mechanisms of ageing and age-associated diseases. CECAD maintains advanced centrally housed in facilities that is in close collaboration with the University of Cologne and to immediate access to CECAD researchers.

The London Research Institute (LRI) is Cancer Research UK's largest research institute, with a focus on the basic biology of cancer. The Institute is based at Lincoln’s Inn Fields in central London and at Clare Hall on the periphery of the city, with a total staff approaching 600. The Institute is a well-known centre of research excellence and was viewed as scientifically outstanding at its 2006 quinquennial review. LRI recruits and develops outstanding group leaders early in their careers, aiming to capture their most productive and creative years. The current portfolio of the LRI comprises 46 research groups working together closely to address related areas of basic cancer research. LRI Technology Core Facilities relevant to this proposal include the following: Bioinformatics and Biostatistics, state-of-the-art mouse-house, Experimental Pathology, Proteomics, and the Transgenic Services.

IGBMC is a research unit CNRS/Inserm/Université Louis Pasteur of ~550 people, in 40 research groups including 300 researchers, postdoctoral fellows and PhD students. The institute, structured in 4 departments, supported by 5 technological platforms, and 12 highly developed common facilities, occupies an eminent position in the landscape of biological and medical research in Europe due to its training structure and its research of international reputation. The institute is integrated in an exceptional academic environment but also holds international and industrial collaborations with e.g. Eli-Lilly, Sanofi-Aventis, Roche. IGBMC, one of the leading European centres of biomedical research is devoted to knowledge applied to human pathologies and provides access to technology platforms highly relevant for the aDDRess ITN.

IFOM is one of the top research centres in Italy, hosted within the IFOMIEO campus together with the prestigious research institution, European Institute of Oncology, the European School of Molecular Medicine and start-up companies. Thirty-five groups are operative in the campus for a total of ~ 500 scientists. Three major assets are critical to the continuous success of the IFOM-IEO campus: i. the scientific excellence of its groups; ii. the state-of-art centralized facilities and iii. the connection to clinical practice, which represents one of the most advanced clinical European centres. IFOM is committed to foster the growth of young scientists, and makes this one of its first priorities. To achieve this goal, the Campus founded the European School of Molecular Medicine (SEMM, www.semm.it) in conjunction with other reputable scientific institutions and with two Italian Universities. SEMM already operates four active Ph.D. programs. Several facilities operate on Campus and are centralized in COGENTECH.

CNIO is the most recognized national centre in Spain and, besides its youth, is rapidly becoming a European reference centre for cancer studies. Through a combination of senior scientists with a well established reputation on cancer biology and an active recruitment of young emergent investigators, the scientific quality is reflected by constant publications on top-tier journals. Several members of the staff are world-leading scientists in their respective fields and receivers of prestigious awards. CNIO is equipped with a dedicated “Biotechnology Programme” that provides all internal services, including Microscopy and Cytometry, Bioinformatics, “omics” and animal transgenic/knockout facilities and a Tumour bank.

The College of Life Sciences at University of Dundee is one of the premier research institutions in the United Kingdom and it has a prominent international reputation. The MRC Protein Phosphorylation Unit in which the Rouse lab is based is also world-renowned and has all of the facilities needed for the experiments proposed. The College of Life Sciences at University of Dundee has a wide range of facilities and equipment, and the MRC Protein Phosphorylation Unit has a dedicated cloning team, protein and antibody production team which will greatly facilitate the experiments proposed. 92 Principal Investigators research a wide range of biological topics with experimental systems ranging from bacteria to mice.

Biomedcode Hellas SA is a Contract Research Organization (CRO) providing full preclinical drug evaluation services using a unique collection of mouse models of human inflammatory diseases mimicking Rheumatoid Arthritis, Intestinal Inflammation, Multiple Sclerosis and others. Biomedcode offers a diverse array of advanced evaluation platforms ideal for the preclinical testing of therapeutics. Primary interests of Biomedcode include the development of novel inflammatory disease models, the comprehensive phenotyping of disease progression, the standardization of novel preclinical drug evaluation platforms and the identification of novel disease pathways and biomarkers.

ATLAS Biolabs GmbH is a leading R&D company of complex analyses in molecular genetics, including next-generation sequencing, targeted sequence capture, microarraybased genomic services, and mass spectrometry. The German company was founded in 2006 as a spin-off of the RZPD, German Resource Center for Genomics, and the CCG, Cologne Center for Genomics. With over 10 years experience in life sciences, ATLAS Biolabs has extensive academic links with various partners and fulfills the requirements for design and manufacturing in-vitro diagnostic medical devices according to ISO 13485:2003/AC:2009. Its major R&D activities include high-level bioinformatics, sequence enrichment, genotyping & gene expression analysis.