The role of the Histone Deacetylases in nucleotide excision repair

Genomic DNA is constantly under threat by a multitude of endogenous and exogenous damaging agents. The underlying sources of damages include ultraviolet (UV) radiation, chemical carcinogen e.g., benzo[a]pyrene (BaP), and chemotherapeutic agents such as cisplatin which mainly result in helix distortion. In human cells, nucleotide excision repair (NER) is the major mechanism to deal with these bulky damages threatening genomic integrity. However, a complex standing question is how is repair orchestrated when DNA is packaged in nucleosomes. Chromatin dynamics, affected by the acetylation status of histones and non-histone proteins, appear to play an important role in repair. Our overarching goal is to identify and dissect the role of histone deacetylating enzymes (HDACs), in repair of nucleosomal templates. These enzymes are overexpressed in cancers and are currently targeted in cancer therapy through specific inhibitors, though the precise mode of action of these inhibitors is unclear. Our lab specializes in mapping DNA damages and NER at single nucleotide resolution in the human genome. Our data indicated that treatment with HDAC inhibitors alters repair efficiency. We will identify changes in genome-wide repair patterns in cells depleted for specific HDACs. Relating these repair patterns to the the chromatin-recruitment of HDACs after damage, our results will provide valuable insights into the function of the HDACs in DNA repair, and could lead to development of new cancer therapy regimens.