The primary focus of our lab is to study the preferential repair of oxidative DNA damage and DNA strand breaks (SBs) in transcribed genes. Various environmental factors such as ultraviolet lights, other radiations and chemical toxins can induce various
types of genomic damage in human cells. However, the cells are also equipped with elaborate repair machinery for maintaining genomic integrity. Oxidative genome damage is repaired via the DNA base excision repair (BER) pathway, initiated with the
excision of the damaged base by DNA glycosylases. We have identified and characterized a family of DNA glycosylases (NEIL1-3) and a new BER subpathway involving the NEILs, and showed that the NEIL1- and 2-initiated pathways are AP endonuclease (APE1)-independent,
but dependent on polynucleotide kinase 3'-phosphatase (PNKP). Furthermore, we established that NEIL2 initiates a new transcription-coupled BER pathway for the preferential repair of oxidized bases from the transcribing genes. We postulate that
this particular repair pathway will have far-reaching consequences in understanding the mechanism of various pathologies, particularly cancers. We recently observed a unique property of a NEIL2 variant that was found to be predominantly present in
lung cancer patients. When characterized biochemically, the variant showed a modest decrease in DNA glycosylase activity; however, total BER was markedly reduced. Surprisingly, the variant gained its repair function under oxidative stress. How this
differential repair activity of the variant is linked to lung pathogenesis is currently under investigation.
Polynucleotide kinase 3'-phosphatase (PNKP) is one of the major DNA end-processing enzymes for blocked DNA ends (3'-phosphate and 5'-hydroxyl) in mammalian cells, and has dual activities: 3'-phosphatase and 5'-kinase. We and others have recently reported
that perturbation in PNKP's activity is linked to various neurological/developmental disorders. PNKP is involved in a multitude of repair processes; its role in DNA base excision (BER) and single-strand break (SSBR) repair is well characterized, but
not in double-strand break repair (DSBR). DNA strand breaks have been linked to various age-associated pathologies, particularly neurodegenerative diseases and cancers. We are examining the role of PNKP in DNA strand break repair in maintaining genomic
integrity via error-free repair.