The complex effects of lysine deacetylase inhibitors on Nucleotide Excision Repair

In recent years lysine deacetylase inhibitors (KDACi) are used in cancer therapy in combination with known chemotherapies such as cisplatin, however the exact molecular mechanism underlying their effect is unknown. Cisplatin induces Bulky DNA damages that distort the helical structure of DNA, eventually causing cancer cell death. 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 that “open” chromatin and facilitate repair. Genome-wide mapping of nucleotide excision repair revealed elevated repair at sites of histone acetylation. KDACs are the “erasers”, responsible for deacetylating lysine residues in proteins, including the N-terminal tails of core histone proteins, resulting in chromatin condensation. Here, we studied the effect of the KDACi sodium butyrate (NaBu) on nucleotide excision repair. NaBu treatment resulted in more accessible chromatin, and better excision repair at early time points. However, at later time points, repair was inhibited, suggesting an involvement of acetylation of non-histone proteins. KDACi are already used in the clinic as anti-cancer drugs. Understanding their effect on excision repair will help planning better chemotherapeutic regimens to enhance their effect in cancer cells.