Beyond the Fanconi anemia pathway: new mechanisms of DNA interstrand crosslink repair

Abstract

DNA contains the instructions necessary for all cellular processes, and it is therefore essential for the growth, reproduction and functioning of every organism. However, a multitude of environmental factors, chemicals, and cellular metabolites damages our DNA every day. If left unrepaired, DNA damage can lead to mutations and contribute to the development of disease, such as cancer. Cellular pathways that maintain DNA integrity are therefore crucial for human health. The work in this thesis investigates how “interstrand crosslinks” (ICLs), extremely toxic DNA lesions, are repaired. ICLs are induced both by compounds formed during cellular processes and by chemicals such as agents used in cancer therapy. ICLs stick together the two strands of DNA, inhibiting fundamental cellular processes that require strand separation, such as the production of proteins and the creation of new cells. Fortunately, cells evolved mechanisms to repair these lesions. We studied these DNA repair mechanisms using extracts derived from the eggs of the Xenopus laevis frog. These extracts contain all the factors necessary to repair ICLs, and therefore allow us to study this process in a test tube. Using this system, we found a novel repair mechanism that acts on naturally occurring ICLs, broadening our understanding of the mechanisms that contribute to the repair of these lesions. In addition, we have studied how the surrounding DNA landscape, or chromatin, changes during the repair of ICLs. These findings not only provide novel insights in how ICLs are repaired, but they could be used in the future to improve cancer treatments.