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Dna Damage REsponse: Actionabilities, Maps and Mechanisms

Project description

Determining the recipe for success in DNA damage control

The integrity of our genetic material must be maintained to ensure proper functioning of our cells and tissues, our viability and procreation, and the transfer of intact and functional genetic material to the next generation. Our trillions of cells receive thousands of DNA lesions daily, whether through physiological processes or insults and toxins. To combat this threat, cells have evolved the DNA-damage response (DDR), a complex collective set of mechanisms that detect DNA lesions, signal their presence and promote their repair. While DNA repair pathways have recently been exploited to treat diseases, the mechanisms are not fully understood. The EU-funded DDREAMM project is investigating DDR pathways to identify factors for sensitivity to DNA-damaging agents, DDR deficiency, and resistance to DDR-targeting treatments. Outcomes should lead to tools allowing precise control of DNA repair, and to therapies for numerous diseases.

Objective

To monitor and protect their genomes, eukaryotic cells have evolved sophisticated DNA-damage response (DDR) systems that comprise DNA repair and DNA-damage signaling processes. DDR deficiencies are associated with diverse human disorders, ranging from aggressive hereditary and sporadic cancers to inherited genetic diseases. The impact of DNA repair has also recently been harnessed to treat diseases through “synthetic lethal” cancer treatments and CRISPR-Cas genome editing. However, the fundamental interactions between DDR pathways that underpin such therapeutic opportunities are still not well understood. Furthermore, we are only just beginning to understand how suppressive functional interactions (so-called “synthetic viability”) can lead to resistance to DDR-targeting therapeutics. Our proposed research will address these important issues by using cutting-edge technologies in gene editing and chemical biology, and by taking a multidisciplinary approach to create deeply integrated genetic and physical maps of DDR pathways and interactions in many human cell types. Next-generation CRISPR-Cas transcriptional genome-wide approaches will be used to uncover hypo- and hyper-morph alleles that affect cellular sensitivity to DNA-damaging agents and DDR-enzyme inhibitors, thus providing insights into DDR events and explaining human DDR-deficiency phenotypes. Mass spectrometry and in-depth mechanistic studies will establish physical interaction networks within the genetic framework and reveal the signaling logic that underpins DDR outcomes and vulnerabilities. With chemical-genetic approaches, we will develop small molecule tools to precisely interrogate DDR pathways and that could lead to new therapeutic agents. In sum, our work should provide major insights into human genome surveillance in multiple cell types, yield powerful tools to precisely control DNA repair outcomes, and speed the development of new therapies for cancer and other diseases.

Host institution

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Net EU contribution
€ 4 420 150,00
Address
Raemistrasse 101
8092 Zuerich
Switzerland

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Region
Schweiz/Suisse/Svizzera Zürich Zürich
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 4 420 150,00

Beneficiaries (4)