Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Combined genetic and biochemical approaches to uncover and characterize redundant factors involved in late stages of recombinational repair.

Funder Wellcome Charity-funded
Recipient organisation University of Dundee
Funding £1.4M
Period Aug 2010 — Apr 2017

In plain English

AI plain-English summary

Every time a cell divides, its DNA can snap in two—and this project studies how cells fix those breaks without introducing errors. DNA double-strand breaks are among the most dangerous types of genetic damage. They arise from radiation, chemicals, and even normal cell division. Cells have a high-fidelity repair system called homologous recombination, but the final steps—where the broken ends are untangled and sealed—remain poorly understood. The problem is that multiple redundant mechanisms can do the job, making it hard to identify which molecules are essential. The researchers have already found one key player, an enzyme called GEN1, in roundworms and human cells. They now plan genetic screens to uncover other factors that work alongside GEN1, and to understand how it helps both repair DNA and signal that damage has occurred. This is fundamental science. It will not directly change medical practice or industrial processes tomorrow. But understanding how cells preserve genetic integrity is the foundation for grasping why repair fails in cancer and ageing. Similar curiosity-driven work on DNA repair enzymes has, in the past, led directly to drugs like PARP inhibitors now used in cancer therapy.

View original technical description
Homologous Recombination (HR) provides an error free DNA repair pathway to deal with DNA double strand breaks (DSBs). Such breaks arise from genotoxic agents, but also happen during normal DNA replication. We know very little about late steps of HR, where redundant mechanisms seem to be able to resolve Holliday Junction (HJ) intermediates. It is only very recently that canonical HJ resolvases have been indentified in animals. One of those enzymes is GEN1 which was purified from human cell ext racts. However, its in vivo function remained unclear. Having followed a forward genetic approach, we found that the C. elegans homolog is required for DSB repair and unexpectedly also has a role in DNA damage checkpoint signalling. We propose a series of genetic screens to find further genes that act in the gen-1 DNA damage checkpoint and DSB repair pathways. Furthermore, we aim to undertake synthetic lethal screens to find genes that act in parallel to gen-1 to mediate the processing of late r ecombination intermediates. Finally, we hope to better understand how GEN-1 works by employing purification procedures from worms and from chicken DT40 cells. This cell-line will also be used to generalize genetic interactions and phenotypes we find in worms.

View the original record at the funder ↗

Researchers

Anton Gartner (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

RecombInsight: Discovery in Mammalian Homologous Recombination DNA Repair
Mechanics and execution of homologous recombination - biophysics to the organism
Identification of eukaryotic Holliday junction processing enzymes using an in vivo model system
Identifying genetic determinants ensuring correct DNA damage repair pathway choice
Structures, Recruitment and Regulation of Key Components in DNA Damage Response

Original classification

Senior Research Fellowship Basic

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