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CFS modelling SIGNED

Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability

Total Cost €

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EC-Contrib. €

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Partnership

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 CFS modelling project word cloud

Explore the words cloud of the CFS modelling project. It provides you a very rough idea of what is the project "CFS modelling" about.

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Project "CFS modelling" data sheet

The following table provides information about the project.

Coordinator
KOBENHAVNS UNIVERSITET 

Organization address
address: NORREGADE 10
city: KOBENHAVN
postcode: 1165
website: www.ku.dk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Denmark [DK]
 Total cost 1˙499˙711 €
 EC max contribution 1˙499˙711 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2015-STG
 Funding Scheme ERC-STG
 Starting year 2016
 Duration (year-month-day) from 2016-05-01   to  2021-04-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KOBENHAVNS UNIVERSITET DK (KOBENHAVN) coordinator 1˙499˙711.00

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 Project objective

Cancer and other diseases are driven by genomic alterations initiated by DNA breaks. Within our genomes, some regions are particularly prone to breakage, and these are known as common fragile sites (CFSs). CFSs are present in every person and are frequently sites of oncogenic chromosomal rearrangements. Intriguingly, despite their fragility, many CFSs are well conserved through evolution, suggesting that these regions have important physiological functions that remain elusive. My previous background in genome editing, proteomics and replication-born DNA damage has given me the tools to propose an ambitious and comprehensive plan that tackles fundamental questions on the biology of CFSs. First, we will perform a systematic analysis of the function of CFSs. Most of the CFSs contain very large genes, which has made technically difficult to dissect whether the CFS role is due to the locus itself or to the encoded gene product. However, the emergence of the CRISPR/Cas9 technology now enables the study of CFSs on a more systematic basis. We will pioneer the engineering of mammalian models harbouring large deletions at CFS loci to investigate their physiological functions at the cellular and organism levels. For those CFSs that contain genes, the cDNAs will be re-introduced at a distal locus. Using this strategy, we will be able to achieve the first comprehensive characterization of CFS roles. Second, we will develop novel targeted approaches to interrogate the chromatin-bound proteome of CFSs and its dynamics during DNA replication. Finally, and given that CFS fragility is influenced both by cell cycle checkpoints and dNTP availability, we will use mouse models to study the impact of ATR/CHK1 pathway and dNTP levels on CFS instability and cancer. Taken together, I propose an ambitious, yet feasible, project to functionally annotate and characterise these poorly understood regions of the human genome, with important potential implications for improving human health.

 Publications

year authors and title journal last update
List of publications.
2017 Stephanie Munk, Jón Otti Sigurðsson, Zhenyu Xiao, Tanveer Singh Batth, Giulia Franciosa, Louise von Stechow, Andres Joaquin Lopez-Contreras, Alfred Cornelis Otto Vertegaal, Jesper Velgaard Olsen
Proteomics Reveals Global Regulation of Protein SUMOylation by ATM and ATR Kinases during Replication Stress
published pages: 546-558, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2017.09.059
Cell Reports 21/2 2019-05-04
2018 Eliene Albers, Mauro Sbroggiò, David Pladevall-Morera, Anna H. Bizard, Alexandra Avram, Patricia Gonzalez, Javier Martin-Gonzalez, Ian D. Hickson, Andres J. Lopez-Contreras
Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality
published pages: 3274-3284, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2018.08.071
Cell Reports 24/12 2019-05-04
2019 David Pladevall-Morera, Stephanie Munk, Andreas Ingham, Lorenza Garribba, Eliene Albers, Ying Liu, Jesper V Olsen, Andres J Lopez-Contreras
Proteomic characterization of chromosomal common fragile site (CFS)-associated proteins uncovers ATRX as a regulator of CFS stability
published pages: , ISSN: 0305-1048, DOI: 10.1093/nar/gkz510
Nucleic Acids Research 2019-08-29

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