Active Genetics & Molecular Biology Cells, Biochemistry & Physiology

Quantitative approaches to investigate the recruitment of RIF1 to chromatin

Funder Wellcome Charity-funded
Recipient organisation University of Edinburgh
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

A protein called RIF1 must latch onto the right parts of a cell’s DNA at the right time, but no one knows exactly how it does this. RIF1 helps coordinate when DNA gets copied, how chromosomes are folded, and how cells repair damaged DNA. When these processes go wrong, cells can become unstable—a hallmark of cancer and other genetic disorders. Current research has identified several possible docking points for RIF1 on chromatin, but it remains unclear which ones actually matter and how they work together. This project will use biochemical experiments to test how purified RIF1 fragments bind to artificial chromatin in a test tube, then confirm those findings by mutating RIF1 in mouse embryonic stem cells to see which interactions are essential. If successful, this work will reveal the molecular rules governing RIF1 recruitment. This is fundamental science: it will not produce a drug or a diagnostic tomorrow. But understanding how a master regulator of genome stability finds its targets could eventually inform therapies for diseases where DNA replication or repair goes awry.

View original technical description
The chromatin-associated protein RIF1 is important for the regulation of key processes in the nucleus. This includes the coordination of DNA replication timing, organisation of chromatin contacts and regulation of the DNA damage response. However, the molecular mechanisms behind these functions remain poorly characterised. My project aims to gain insight into these mechanisms by exploring RIF1 recruitment to chromatin which has recently been shown to be cell cycle regulated. Preliminary data has shown that the C-terminal conserved regions of RIF1 interact with several heterochromatin-associated proteins and RIF1 has also been suggested to interact with the acidic patch of nucleosomes. However, it is unclear how these features coordinate to achieve RIF1 recruitment, and which are necessary for this recruitment. I will use a variety of in vitro biochemical assays to characterise the binding of purified RIF1 fragments to assemblies of chromatin. I will then translate my findings in vivo by mutating RIF1 in mESCs to determine the cellular importance of different interactions. Overall, I hope to determine the key interactions driving RIF1 recruitment to chromatin during different cell cycle stages.

View the original record at the funder ↗

Researchers

Susanna Alsop (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

How do Rif1 and SAF-A remodel chromatin to ensure effective DNA repair?
Molecular determination of Rif1-Associated Genomic Elements and their function in regulating genome activity and integrity
How does RIF1 regulate DNA replication and cell recovery after chemotherapeutic replication inhibition?
Molecular control of DNA replication timing in mammalian cells
DNA replication timing and spatial organization of chromatin

Original classification

PhD Studentship (Basic)

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