Final Report Summary - CHROMATINREPAIRCODE (CHROMATIN-REPAIR-CODE: Hacking the chromatin code for DNA repair)
Our cells receive tens of thousands of different DNA lesions per day. Failure to repair these lesions will lead to cell death, mutations and genome instability, which contribute to human diseases such as neurodegenerative disorders and cancer. Efficient recognition and repair of DNA damage, however, is complicated by the fact that genomic DNA is packaged, through histone and non-histone proteins, into a condensed structure called chromatin. The DNA repair machinery has to circumvent this barrier to gain access to the damaged DNA and repair the lesions. Our recent work suggests that chromatin-modifying enzymes (CME) help to overcome this barrier at sites of DNA damage. However, the identity of these CME, their mode of action and interconnections with DNA repair pathways remain largely enigmatic. In this project we systematically identified and characterized the CME that operate during DNA repair processes in both yeast and human cells. To reach this goal, we used a cross-disciplinary approach that combined novel and cutting-edge genomics approaches with bioinformatics, genetics, biochemistry and high-resolution microscopy to unveil novel CME that may potentially regulate repair of DNA damage. A series of functional assays characterized their role in distinct DNA repair pathways, focusing on those that counteract DNA strand breaks and replication stress. Together these studies provide insight into how CME assist cells to repair DNA damage in chromatin and inform on the relevance of CME to maintain genome stability and counteract human diseases.