Understanding DNA interstrand crosslink repair – the Fanconi anemia pathway and beyond

Project Information

XlinkRepair

Grant agreement ID: 101003210

DOI

10.3030/101003210

Project closed

EC signature date 27 January 2021

Start date 1 May 2021

End date 30 April 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands

Periodic Reporting for period 3 - XlinkRepair (Understanding DNA interstrand crosslink repair – the Fanconi anemia pathway and beyond)

Reporting period: 2024-05-01 to 2025-10-31

Summary of the context and overall objectives of the project

Our genome is constantly damaged by agents from within or outside our cells causing DNA lesions. Failure to repair these lesions by any of the numerous cellular DNA repair pathways can lead to genome instability and the development of genetic diseases such as cancer. A particularly hazardous type of DNA damage is an interstrand crosslink (ICL) that can be induced by widely used cancer chemotherapeutics but also by endogenous metabolites. It was long thought that there was only one pathway that could repair these lesions, the Fanconi anemia pathway, a DNA repair pathway affected in the cancer predisposition syndrome Fanconi anemia (FA). The FA pathway is a complex multi-subunit DNA repair pathway of which many mechanistic details are still missing. Recently, we discovered an additional ICL repair pathway which repairs endogenous ICLs induced by acetaldehyde, a product of alcohol metabolism. However, the molecular mechanism of this pathway is mostly unknown. In this project we will investigate the missing details of the Fanconi anemia ICL repair pathway and define the mechanism(s) of repair of aldehyde induced ICLs. These studies will provide important novel insights into how cells maintain genome integrity, increase our understanding of Fanconi anemia, and could provide new clues to improve strategies in chemotherapeutic treatment.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have investigated the role of the Fanconi anemia core complex in ICL repair and found that there might be hidden functions of this complex. Further investigation is required to validate and gain insights in the mechanistic details of this difference. Furthermore, we showed that not only acetaldehyde induced ICLs, but also ICL induced by other reactive aldehydes are repaired by our recently identified ICL repair pathway, indicating this is a more general aldehyde-ICL repair pathway. In addition, we have identified several factors potentially involved in this novel ICL repair pathway and we are currently testing their function. Finally, we have developed tools to investigate nucleosome dynamics during ICL repair and optimized methods to identify repair-induced DNA mutations. We have used these tools to investigate the mechanism of ICL repair.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our newly developed methods and recent results are state of the art, provide, or will be used to provide, important new insights into the mechanism of repair of this dangerous but also clinically relevant DNA lesion. During the second part of this project, we aim to validate our current results and define additional mechanistic details of the FA pathway. We will identify factors involved in the new ICL repair pathway and define their mode of action. Finally, we aim to determine the role of nucleosome remodeling in ICL repair and gain insights in the mechanism underlying this.