Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Mechanisms of DNA interstrand crosslink repair in humans.

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £1.6M
Period Dec 2018 — Dec 2023

In plain English

AI plain-English summary

Every time a cell divides, it must repair a specific type of DNA damage—a chemical crosslink that glues the two strands of the double helix together—or risk triggering cancer. This project unpacks the molecular machinery that human cells use to find and fix these interstrand crosslinks (ICLs). When that repair system fails, it causes Fanconi Anaemia, a condition that dramatically raises cancer risk. Conversely, cancer doctors deliberately create ICLs with chemotherapy drugs, but tumours often become resistant by repairing the damage too efficiently. The researcher has already identified the proteins that first detect ICLs and has imaged their structure using cryo-electron microscopy. Over the next five years, they will watch these repair factors in action at the single-molecule level, determining exactly how they are activated and recruited to the damage site. This is fundamental science—there is no immediate clinical application. But understanding the precise choreography of ICL repair could eventually allow clinicians to block the pathway in resistant tumours, making chemotherapy more effective, or to boost it in patients with inherited repair defects. Similar mechanistic work on other DNA repair pathways has already led to targeted cancer drugs.

View original technical description
My research is focused on uncovering the molecular mechanisms of DNA interstrand crosslink (ICL) repair in humans. Disruption of the underlying DNA-repair pathway causes Fanconi Anemia (FA), with serious cancer susceptibility. Also, ICL-forming drugs are used therapeutically in non-FA cancer patients, however resistance is a major problem. Targeting the FA-pathway could allow clinicians to treat these patients. A key and fundamental event in the FA-pathway is the recruitment of repair proteins to ICLs. Specific and timely recruitment is essential for accurate repair. We have recently discovered proteins specifically detecting ICLs and we have obtained the cryo-EM structure of other ICL-repair proteins. My aim over the next five years is to advance the field further by uncovering mechanistically how repair factors are activated and recruited to ICLs at the single-molecule level. We will: 1) Dissect the mechanism of initial recruitment of repair factors to ICLs. 2) Uncover functions of identified proteins in FANCD2-complexes in ICL-repair. 3) Determine roles of novel phosphorylation sites on FANCD2/FANCI. 4) Elucidate mechanism of FANCD2/FANCI activation. Addressing these central questions will not only greatly advance our understanding of ICL-repair, but will also likely enhance our understanding of other DNA repair pathways utilizing analogous mechanisms.

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Researchers

Martin Cohn (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Regulation of DNA interstrand crosslink repair by ubiquitin.
Uncovering function and mode of activation of the central Fanconi Anemia FANCD2/FANCI DNA repair protein complex, a potential cancer drug target.
DNA interstrand crosslink repair and chromatin remodelling
Defining the structural mechanism of the cellular response to DNA inter-strand crosslinks: structural characterization and inhibition of SLF1-SLF2 with its interacting partners.
Unravelling the structural features and repair pathways of alcohol and fatty acid-derived DNA interstrand crosslinks

Original classification

Senior Research Fellowship Basic

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