Role of Acetylation in Neuronal DNA Repair
One of the most critical processes fundamental to cellular function, integrity, and indeed, survival, is the appropriate response to and repair of DNA damage that arises from normal aspects of DNA metabolism, endogenous sources such as reactive oxygen species, or exogenous genotoxic agents such as mutagens and ionizing radiation. Double strand breaks (DSBs) are the most genotoxic DNA lesions. Unrepaired DSBs can lead to cell death, whereas misrepaired DSBs increase the likelihood of chromosome rearrangement, mutagenesis and loss of crucial genetic information. In replicating cells, such instability can result in apoptosis or cellular transformation. In the case of neurons residing in the adult brain, this is even more critical, given that they are post-mitotic and terminally differentiated, and cannot be readily replaced after trauma or disease. Indeed, accumulation of genomic (and mitochondrial) DNA damage is an important feature of both acute and chronic neurodegeneration.
A significant body of evidence suggests that histone acetylation, which is regulated by the concerted actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a central role in the chromatin remodeling that occurs in response to DNA damage. Chromatin-modifying drugs such as HDAC inhibitors (HDACis) have emerged as attractive therapeutic compounds for neurodegeneration in the last decade. Nevertheless, more studies are needed to determine the effect of HDACis on DNA damage repair in neurodegeneration.
One limitation in understanding DNA repair in neurons, is that most of what is known comes from studies performed in cycling cells or tumors, and might be therefore irrelevant to post-mitotic cells. One of our goals in the Langley laboratory is to study the molecular mechanisms specific to neuronal DNA repair and the effects of HDAC inhibition in neurons, which is crucial for the development of efficient neurotherapeutic strategies.