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ICLUb SIGNED

Regulation of DNA interstrand crosslink repair by ubiquitin.

Total Cost €

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EC-Contrib. €

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Partnership

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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 UK (GLASGOW) coordinator 1˙771˙592.00
2    UNIVERSITY OF DUNDEE 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

year authors and title journal last update
List of publications.
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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