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DPC_REPAIR SIGNED

Mechanism of DNA-protein cross-link repair in S phase

Total Cost €

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EC-Contrib. €

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Partnership

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Project "DPC_REPAIR" 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˙498˙856 €
 EC max contribution 1˙498˙856 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-STG
 Funding Scheme ERC-STG
 Starting year 2017
 Duration (year-month-day) from 2017-01-01   to  2021-12-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KOBENHAVNS UNIVERSITET DK (KOBENHAVN) coordinator 1˙498˙856.00

Map

 Project objective

DNA-protein cross-links (DPCs) are common DNA lesions caused by endogenous, environmental, and chemotherapeutic agents. Cells are susceptible to these lesions during S phase, as DPCs impede replication fork progression and are likely to induce genomic instability, a cause of cancer and aging. Despite its relevance to human health, the repair of DPCs is poorly understood. Research on DPC repair has mainly involved testing cellular responses to compounds such as formaldehyde, but these agents induce a wide variety of DNA lesions, and conflicting results have been reported. To overcome these obstacles, I have developed the first in vitro system that recapitulates replication-coupled DPC repair. In this system, a plasmid containing a site-specific DPC is replicated in Xenopus egg extracts. Using this approach, I demonstrated that DPC repair requires DNA replication. When a replication fork encounters a DPC, the DPC is degraded into a peptide-adduct, which allows replication bypass by translesion DNA synthesis. Importantly, these experiments identified a novel proteolytic pathway whose activity is regulated by replication. This in vitro system now provides a powerful means to identify and characterize the different factors that participate in S phase DPC repair. I speculate that for DPC processing to occur, the protein-adduct must first be detected, then marked for degradation and ultimately degraded. Using a series of complementary strategies, which will take advantage of the in vitro system combined with proteome and genome wide approaches, I seek to uncover the different players that participate in each of these events. This project will enable a detailed mechanistic outlook of a complex multi-step reaction that has not been feasible to achieve using existing methodologies. It will also improve our understanding of how DPCs impact genomic stability and the consequences of not repairing these lesions for human health.

 Publications

year authors and title journal last update
List of publications.
2019 Justin L. Sparks, Gheorghe Chistol, Alan O. Gao, Markus Räschle, Nicolai B. Larsen, Matthias Mann, Julien P. Duxin, Johannes C. Walter
The CMG Helicase Bypasses DNA-Protein Cross-Links to Facilitate Their Repair
published pages: 167-181.e21, ISSN: 0092-8674, DOI: 10.1016/j.cell.2018.10.053
Cell 176/1-2 2020-04-24
2019 Hazal B. Kose, Nicolai B. Larsen, Julien P. Duxin, Hasan Yardimci
Dynamics of the Eukaryotic Replicative Helicase at Lagging-Strand Protein Barriers Support the Steric Exclusion Model
published pages: 2113-2125.e6, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2019.01.086
Cell Reports 26/8 2019-11-08
2019 Nicolai B. Larsen, Alan O. Gao, Justin L. Sparks, Irene Gallina, R. Alex Wu, Matthias Mann, Markus Räschle, Johannes C. Walter, Julien P. Duxin
Replication-Coupled DNA-Protein Crosslink Repair by SPRTN and the Proteasome in Xenopus Egg Extracts
published pages: 574-588.e7, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2018.11.024
Molecular Cell 73/3 2019-11-08

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The information about "DPC_REPAIR" are provided by the European Opendata Portal: CORDIS opendata.

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