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ICLUb SIGNED

Regulation of DNA interstrand crosslink repair by ubiquitin.

Total Cost €

EC-Contrib. €

Partnership

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Outcomes and
results

ICLUb project word cloud

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

assembled recognised disorder liver fancd2 icls understand cure aldehyde activation ubiquitin icl mechanisms considerable chemical interstrand stably fa devastating repair atomic marrow quantities regulation dna tackle readers producing genome model bone modification removal concerning monoubiquitin mechanistic instability crosslinks despite fanconi dimensional characterise anemia site cancers typified unknown predisposition cycle homozygous strikingly hallmark monoubiquitination core mutations signal critical complexes structure entirety genetics modified little biophysical childhood poorly breakthrough mechanism disassembled regulated therapeutic deubiquitination

Project "ICLUb" data sheet

The following table provides information about the project.

Coordinator	UNIVERSITY OF GLASGOW Organization address address: UNIVERSITY AVENUE city: GLASGOW postcode: G12 8QQ website: www.gla.ac.uk 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	United Kingdom [UK]
Total cost	1˙999˙998 €
EC max contribution	1˙999˙998 € (100%)
Programme	1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
Code Call	ERC-2015-CoG
Funding Scheme	ERC-COG
Starting year	2016
Duration (year-month-day)	from 2016-09-01 to 2021-08-31

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	UNIVERSITY OF GLASGOW UNIVERSITY OF GLASGOW Organization address address: UNIVERSITY AVENUE city: GLASGOW postcode: G12 8QQ website: www.gla.ac.uk contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	UK (GLASGOW)	coordinator	1˙771˙592.00
2	UNIVERSITY OF DUNDEE UNIVERSITY OF DUNDEE Organization address address: Nethergate city: DUNDEE postcode: DD1 4HN website: www.dundee.ac.uk contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	UK (DUNDEE)	participant	228˙405.00

Map

Project objective

The overall objective of this proposal is to understand, on an atomic level, the mechanism of activation and regulation of the Fanconi Anemia (FA) DNA repair pathway. Homozygous mutations in the FA pathway lead to Fanconi Anemia, a devastating childhood genome instability disorder, typified by bone marrow failure and a high predisposition to cancers. The FA pathway is required for the repair of DNA interstrand crosslinks (ICLs), the hallmark of many cancers and FA. ICL repair is poorly understood on a biophysical and mechanistic level. The FA pathway is regulated by ubiquitin, in a cycle of monoubiquitination and deubiquitination of FANCD2. Despite considerable advances in our understanding of the genetics of the pathway, there is strikingly little known on a mechanistic and chemical level concerning how the ubiquitin signal is assembled, recognised and disassembled. We will define, on an atomic level, the site-specific monoubiquitination and deubiquitination cycle of FANCD2 in its entirety. We will determine the mechanism of FANCD2 monoubiquitination, identify and characterise currently unknown readers of the monoubiquitin signal, define the role of the core complex in the modification of FANCD2, and the requirements for removal of the signal. To tackle this ambitious work we will determine the atomic level three-dimensional structure of key complexes in the modification cycle, and develop a novel method for producing large quantities of stably modified FANCD2. The results of our work will represent a major breakthrough in our knowledge and understanding of the regulation of a critical DNA repair process, will provide a model for understanding mechanisms of monoubiquitination, and will open up both therapeutic potential and new pathways for research into the cause and cure of FA, cancers, and aldehyde-induced liver or bone marrow failure.

Publications

List of publications.
year	authors and title	journal	last update
2017	Francesca E. Morreale, Alessio Bortoluzzi, Viduth K. Chaugule, Connor Arkinson, Helen Walden, Alessio Ciulli Allosteric Targeting of the Fanconi Anemia Ubiquitin-Conjugating Enzyme Ube2T by Fragment Screening published pages: 4093-4098, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b00147	Journal of Medicinal Chemistry 60/9	2019-06-18
2018	Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1 published pages: e201800162, ISSN: 2575-1077, DOI: 10.26508/lsa.201800162	Life Science Alliance 1/5	2019-05-15

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