Base Excision DNA Repair in Disease Susceptibility and Treatment

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Using molecular, biochemical and structural approaches, we have helped define how human BER proteins recognize and coordinately process target lesions. The research has centered on two protein apurinic/apyrimidinic endonuclease 1 (APE1), the major mammalian protein for repairing abasic sites in DNA, and x-ray cross-complementing 1 (XRCC1), a non-enzymatic scaffold that facilitates the efficient execution of single-strand break repair. One of the main basic science goals of the lab is to establish genetically modified cell lines to dissect out the precise contribution of each proposed function of APE1 (i.e. its nuclease activity, redox regulatory role, etc.) in cell growth/viability, genome maintenance, and protection against DNA-damaging agents. Defining which of the many reported functions of APE1 are critical to normal cellular activity is a key step towards understanding the potential relationship of the protein to the aging process and disease risk. With respect to XRCC1, we are investigating its role in mitochondrial dysfunction and how that may contribute to the development or severity of neurological disease. This may stem from the accumulation of DNA damage and an associated activation of poly (ADP-ribose) polymerase 1, (PARP-1), which leads to NAD consumption and impairment of mitochondrial function. XRCC1, unlike many of its interacting partners including TDPI, Aprataxin, PNPK, and POLB, which have been shown to localize to the mitochondria, has been reported to exclusively reside in the nucleus. Thus, we are probing the nucleus-to-mitochondria signaling and examining whether a deficiency in XRCC1 promotes mitochondrial dysfunction that may contribute to disease pathology.