Involvement of Histone Acetyl Transferases in Nucleotide Excision Repair

DNA damages impair genome stability and increase the risk of mutations that lead to cancer. Bulky damages that distort the helical structure of DNA are induced by UV radiation, the chemotherapy drug Cisplatin and other environmental mutagens. In human cells, these damages are repaired by nucleotide excision repair (NER). The mechanism of excision repair in naked DNA is well understood. However, it is less clear how repair occurs in the nucleus, where DNA is wrapped around histones to form nucleosomes and higher order chromatin. Although this packaging hinders the access of repair proteins, eventually, the majority of damages in the genome are repaired. The current working hypothesis is that there are active mechanisms in place to “open” chromatin and facilitate repair. Histone acetyl transferases (HATs) are the “writers”, responsible for acetylating lysine residues in the N-terminal tails of core histone proteins. These acetylation marks inhibit the folding of nucleosome arrays, resulting in chromatin decondensation. Therefore, histone acetylation may directly, or indirectly, through chromatin-remodeling proteins, affect NER and allow better access for excision repair proteins. The main objective of our research is to determine the role of histone acetylation in nucleotide excision repair. High-resolution maps of excision repair will be created using the XR-seq method in HAT knock-out cell lines. This data and ChIP-seq data for specific histone acetylation marks and genome-wide HAT recruitment will allow us to detect differential repair regions across different genomic contexts and allow us to characterize the specific involvement of histone acetylation in NER.