Active Genetics & Molecular Biology Cells, Biochemistry & Physiology

Chromosome Breaks and the DNA Damage Response in Transcribed Genes

Funder MRC (part of UKRI)
Recipient organisation University of Sussex
Funding £1.7M
Period May 2023 — Mar 2027

In plain English

AI plain-English summary

Every time a cell copies a gene into messenger RNA, it risks breaking a chromosome. These DNA double-strand breaks can kill the cell or, if repaired incorrectly, trigger the chromosomal rearrangements that drive cancer. Scientists already understand how cells mend breaks in quiet stretches of DNA, but they know almost nothing about how repair happens inside genes that are actively being transcribed. This project will uncover how the cell’s repair machinery coordinates with the transcription machinery—the molecular complex that reads genes—to fix breaks accurately using homologous recombination. The researchers will also examine how the chromatin structure, the protein spool around which DNA is wound, influences this process. This is fundamental science: there is no immediate clinical application. But understanding how transcription and repair collide could eventually explain why certain cancers, particularly those with defects in DNA repair, are vulnerable to therapies that deliberately create breaks in active genes. Similar fundamental work on DNA repair pathways has already led directly to drugs like PARP inhibitors, which exploit repair weaknesses in breast and ovarian cancers.

View original technical description
DNA double-strand breaks (DSBs) can arise through normal DNA metabolism or through exposure to DNA damaging agents such as ionizing radiation (IR), and can lead to breaks in our chromosomes which store our genetic information. These lesions are normally repaired by one of two DSB repair pathways termed non-homologous end joining (NHEJ), or homologous recombination (HR) repair pathways. DSB repair is important as failure to repair such lesions can cause cell death, and their misrepair can trigger chromosomal rearrangements, which can lead to cancer. While considerable advances have been made in our understanding of DSB repair, how it occurs in the context of transcription, in which the genetic material within genes is copied into messenger RNA to facilitate protein production, is unclear. The aim of the proposed research is to understand how cells respond to chromosome breaks within transcribed genes and facilitate their accurate repair by homologous recombination. In particular, we will explore the roles of chromatin (structures in which DNA is wrapped up in) and the transcription machinery (which copies DNA into messenger RNA) in coordinating these responses. The proposed research will provide mechanistic insights into DSB detection and repair within transcribed genes, and further, how defects in these processes can be exploited to target particular cancers.

View the original record at the funder ↗

Researchers

Timothy Humphrey (Principal Investigator)

Related Research

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Role of the BAF180 remodelling complex in transcriptional repression and DNA double strand break repair in mammalian cells.
The role of protein-protein interactions in regulation of DNA double-strand break repair in chromatin
Structures and mechanisms of key components in the DNA damage response.

Original classification

Research Grant

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