The European Research Council (ERC) has awarded Anton Goloborodko, Junior Group Leader at IMBA, a Starting Grant for his project on homology search in DNA repair. The ERC Starting Grant is the most prestigious European research grant for early career scientists. The funded project is the next step in the Goloborodko Lab’s ongoing research into the biophysics of DNA structure.
Homology-Directed Repair: The Enigmatic Solution
Both environmental and biological factors can damage DNA, leading to the loss of important genetic material. To preserve genetic information, cellular DNA repair mechanisms seek to quickly and effectively repair DNA damage. One of these mechanisms is the so-called Homology-Directed Repair (HDR). HDR uses a homologous copy of the damaged site as a template for accurate repair.
“During HDR, the damaged DNA region is recognized and stabilized by the repair machinery, which forms a large protein complex,” Goloborodko explains. However, the next step in HDR is poorly understood: “We don’t know how the repair machinery then manages to quickly comb through the enormous and tightly packed genome to find the homologous template and bring it close to the damaged site.”
In the last years, different theories have been developed to explain the unknowns of the HDR process. “Different theories propose that the thermal-based diffusion of molecules or the rearrangement of the DNA by molecular motors could explain how the homologous template reaches the damaged DNA site, but these theories haven’t been proven yet,” Goloborodko explains.
In the newly funded ERC project, the Goloborodko group will apply their biophysics and computational biology knowledge to develop new physics-based computational simulations. “Using these simulations, we will test which of these theories agree with what we know about the structure and mechanics of chromosomes, focusing on how the damaged DNA site and the rest of the DNA move within the complex nuclear environment.” Goloborodko explains. By altering the forces in their simulations and adjusting their parameters, the team will be able to predict the effect of various biological factors in the homology search process key to HDR.
From experiments to modeling, and back again
The last years have brought incredible advancements in the field of DNA structure. New technologies like Hi-C have allowed scientists to measure DNA structure to an unprecedented degree. At the same time, technical advances, like those led by Daniel Gerlich at IMBA, now enable scientists to simultaneously study the folding of both copies of the same chromosome. “The data and ideas produced by these research teams have expanded our understanding of DNA folding, and thus our ability to simulate it,” Goloborodko explains.
Goloborodko and his team aim to harness the power of these advancements: “We want to translate these findings into vertebrate cells to find the last clue for understanding HDR,” Goloborodko remarks. “For this, we will study the movement of the damaged DNA site at all possible scales – from the microscopic motion along DNA fibers to large-scale rearrangement in the nucleus.”
The results of Goloborodko’s simulations will, in turn, provide a path for experimentally studying homology search during HDR. For this, Goloborodko will collaborate with various research groups at the Vienna BioCenter, including long-term collaborator Daniel Gerlich at IMBA, as well as David Hasselbach and Francesco Balzarotti at the Research Institute of Molecular Pathology (IMP). In addition, Goloborodko will collaborate with one of the worldwide experts in the field of HDR, Anjana Badrinarayanan at the National Centre for Biological Sciences (NCBS), India.
“Collaborating with these world-leading scientists will allow us to use cutting-edge technologies to experimentally test the ideas we propose, which was impossible before,” Goloborodko explains. “This will hopefully revolutionize our understanding of this key molecular process.”
About the ERC
The European Research Council, established by the European Union in 2007, is the premier European funding mechanism for excellent frontier research. The ERC’s mission is to facilitate the highest quality of research across all fields in Europe through competitive funding. The ERC offers four core grant schemes: Starting Grants, Consolidator Grants, Advanced Grants and Synergy Grants.
“The ERC Starting Grant not only provides financial support to my lab but also highlights the quality of our research,” Goloborodko says. “Ultimately, the grant will help us establish the best conditions to keep recruiting top talent and making important scientific advances.”
ERC Starting Grants provide funding of up to 1.5 million Euro for a period of 5 years to support personnel and research costs of the funded project. Anton Goloborodko’s new ERC Starting Grant is the twenty-third ERC grant awarded to faculty members at IMBA.
About IMBA:
The Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (ÖAW) is one of Europe’s leading biomedical research institutes. IMBA is located at the Vienna BioCenter, Austria's vibrant cluster of universities, research institutes, and biotech companies. IMBA research topics include chromosome biology, RNA biology, selfish elements and silencing mechanisms, functional genomics, cell and developmental biology, stem cell biology, molecular medicine, neuroscience, organoid research, and disease models.
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