The accurate maintenance of nuclear DNA is critical to cellular and organismal function. Defects in DNA integrity are associated with tumorigenesis, immunodeficiencies and aging. Therefore, numerous DNA repair systems have evolved in mammalian cells to cope with daily damage. The DNA and the histones are arranged in the nucleus in a highly condensed structure known as chromatin. Cellular processes that require unwinding of the double helix, such as transcription, replication and DNA repair, must overcome this natural barrier to gain DNA accessibility. Our work focuses on understanding the role played by chromatin modifications and chromatin modifying enzymes in DNA repair mechanisms, and the consequences of the malfunction of these pathways causing disease, particularly in neurodegeneration and aging.
SIRT6 is a chromatin-bound protein with deacetylase, ADP rybosilase and deacylase activities. SIRT6-deficient mice die before 4 weeks of age from profound hypoglycemia and present progeroid-like phenotype. We found that SIRT6 is recruited to the sites of damage as early as 5 seconds after damage, allowing chromatin remodeling and repair. Particularly, the brain is one of the most affected tissues. We observe increased DNA damage and defective signaling in SIRT6-deficient brains. Moreover, primary brain cultures exhibit increased genotoxic sensitivity when exposed to DNA damaging agents. 1-DNA damage molecular mechanism: We are investigating how cells cope to maintain genome integrity. Understanding different pathways involved in DNA repair and chromatin stability may help prevent disease, and allow the development of new therapies. We are investigating the earliest steps in the DNA repair signaling, focusing in how DNA damage is recognized by SIRT6. We are interested in how epigenetic modifications and chromatin structure influence DNA repair, and are investigating the roles of several uncharacterized proteins in the DNA damage signaling. 2. Epigenetic modifications and DNA damage in neurodegeneration. The highest risk factor in developing neurodegeneration is aging. Changes in epigenetic modifications and accumulation of DNA damage may explain this etiology. We are investigating SIRT6 brain specific KO mice, as a mice model for predisposition to DNA damage accumulation to understand brain health.