Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Serine ADP-ribosylation in genome stability and human disease

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £2.1M
Period Oct 2018 — Oct 2023

In plain English

AI plain-English summary

Every human cell carries a set of chemical switches that control how it repairs broken DNA, and a newly discovered switch—called serine ADP-ribosylation—may be the master dial for that repair system. Researchers have found that two proteins, HPF1 and ARH3, work together to add and remove this switch, but no one knows exactly how they do it. This matters because when DNA repair goes wrong, cells accumulate mutations that can lead to cancer and other genetic diseases. Current drugs that block the PARP enzymes responsible for this modification are already used to treat some cancers, but they work bluntly, affecting many processes at once. Understanding the precise molecular choreography of HPF1 and ARH3 could reveal why those drugs work in some patients and fail in others. This project is fundamental science. It will use biochemistry, structural biology, and cell models to map the exact mechanism of the switch and identify which cellular processes it controls. If successful, it will provide a molecular blueprint for designing more targeted therapies that fine-tune DNA repair without the side effects of current treatments. Similar fundamental discoveries about protein modifications have previously led to entire classes of drugs, from kinase inhibitors to PARP inhibitors themselves.

View original technical description
ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr. Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.

View the original record at the funder ↗

Researchers

Ivan Ahel (EPMC Awardee)

Related Research

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ADP-ribosylation signalling in genome stability
Protein poly(ADP-ribosyl)ation in genome stability and human disease.
Molecular mechanisms of cysteine ADP-ribosylation
Regulation of DNA repair by histone ADP-ribosylation
Understanding the role of ADP-ribosylation in regulating DNA repair

Original classification

Senior Research Fellowship Basic Renewal

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