The DNA of all cells is constantly damaged by environmental factors and internally arising chemicals. To counter this, multicellular organisms have evolved sophisticated mechanisms – collectively termed the DNA-damage response (DDR) – to detect DNA lesions, signal their presence, and promote their repair. While DNA repair pathways have recently been exploited to treat certain cancers, DDR mechanisms are not fully understood and much potential for medical applications for this remains to be explored. DNA repair pathways have also recently been harnessed for “genome editing”, with the potential to yield cures for debilitating genetic disorders. But understanding of how to control genome editing through controlling the DDR is still in its infancy.
The EU-funded DDREAMM project is investigating DDR pathways to identify factors that confer sensitivity or resistance to DNA-damaging agents, and to control genome editing. This project is leading to insights into human genome surveillance, is generating tools allowing precise control of DNA repair and genome editing, and will nurture the development of new therapies for cancer and other diseases.
DNA-damaging agents such as ionizing radiation and chemotherapeutic drugs have long been used to treat cancers. More recently, genome editing agents, such as CRISPR-Cas, are being explored as ways to treat genetic disorders and create cell therapies. While recent advances leading to targeted DDR therapeutics and genome editing reagents, there are still few options and a great deal left unknown. This project will lead to a better understanding of DNA repair and genome editing, and may identify novel therapeutic strategies.
Our overall objective is to develop and understand comprehensive maps of cellular DDR pathway interactions in different cell types. Our focus is on 1) selective differences between cancer cells and normal cells, and 2) interactions between genome editors and DDR in normal cells. Genetic differences between cancer and normal cells could identify opportunities for therapeutic exploitation, while our findings genome editors could yield new approaches to treat genetic disorders. To achieve our goals, we are using an interdisciplinary set of genetic, physical, and mechanistic experiments.
