Active Genetics & Molecular Biology Cells, Biochemistry & Physiology

Control of DNA Replication by Protein Dephosphorylation: the Role of Protein Phosphatase 1 and its Regulatory Interactors

Funder Wellcome Charity-funded
Recipient organisation University of Aberdeen
Funding £2.5M
Period Nov 2024 — Nov 2032

In plain English

AI plain-English summary

Cells copy their DNA using a molecular machine that must be switched on and off at exactly the right moments. Scientists understand how the "on" switch works—a process called phosphorylation—but the "off" switch, which removes phosphate groups via enzymes called phosphatases, remains largely mysterious. This project aims to crack that mystery by focusing on one key phosphatase, PP1, and the proteins that guide it to its targets. Why this matters: Errors in DNA replication cause genome instability, a hallmark of many cancers and developmental disorders. Without knowing how PP1 turns off replication or helps cells recover from replication interruptions, researchers cannot design drugs that target these control points. If successful, this work could reveal new therapeutic avenues for diseases driven by genome instability. Understanding PP1’s precise molecular choreography might eventually allow clinicians to restore normal replication control in cancer cells or protect healthy cells during chemotherapy. This is fundamental science—there is no immediate practical application. But past discoveries about replication control have directly led to cancer drugs such as PARP inhibitors, and this project could lay similar groundwork for future treatments.

View original technical description
DNA replication is central to life, with defects in this process a major cause of disease. Decades of study have revealed how phosphorylation of the replication machinery drives replication initiation. Dephosphorylation by protein phosphatases is also essential for DNA replication, but we do not understand why. Phosphatases are implicated in controlling the replication temporal programme, cell recovery from replication interruption, and replication protein recycling. However even for these established functions, we lack knowledge of the substrates dephosphorylated and their effects. These gaps in understanding limit opportunities for therapeutic intervention. I aim for an integrated understanding of how Protein Phosphatase 1 (PP1) controls DNA replication. PP1 is targeted to substrates by a series of regulatory interactors, including RIF1 and NIPP1, which control the replication programme and recovery from DNA damage. My aim is to identify the molecular and structural basis of these controls, and to discover the precise mechanisms through which PP1 regulates normal and interrupted DNA replication. I will also test if other PP1 regulatory interactors control replication. Investigating DNA replication control from this new angle, my research programme will establish how PP1 integrates DNA replication with other cellular events, suggesting avenues for treatment of diseases caused by genome instability.

View the original record at the funder ↗

Researchers

Anne Donaldson (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Defining A Role For DNA Phosphorylation In Maintaining Replication Fork Stability
Protein phosphatase 1 (pp1) in the regulation of mitotic exit and nuclear organisation
Novel Role of a Protein Phosphatase in Chromosome Segregation
How Sld3 integrates kinase signalling to control DNA replication initiation
Understanding the role of PrimPol in damage tolerance during genome replication in eukaryotic cells

Original classification

Discovery Award

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.