研究领域

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Oxidative DNA damage is involved in development of human diseases that include cancer, neurodegenerative diseases, atherosclerosis, diabetes and others. Oxidative DNA damage may result in genomic and epigenomic instability that subsequently leads to initiation and progression of human diseases. To combat the adverse effects of oxidative DNA damage, human cells have developed DNA base excision repair (BER), the major pathway that repairs oxidative DNA base lesions and strand breaks. Thus, understanding the molecular mechanisms by which oxidative DNA damage and BER may cause and prevent genomic and epigenomic instability is the key for further understanding initiation and progression of human cancer, neurodegenerative diseases and other diseases. Current research in my laboratory focuses on the following areas for understanding the molecular mechanisms underlying oxidative DNA damage-induced genomic and epigenomic instability and its prevention. Study on trinucleotide repeat instability via oxidative DNA damage and repair We recently found that repair of oxidative DNA damage by BER resulted in CAG repeat expansion and deletion that is directly linked to human diseases, i.e., Huntington’s disease, Kennedy’s disease and breast and prostate cancer. Specifically, we found that inefficient activities of BER enzymes, DNA polymerase β (Pol β) and flap endonuclease 1 (FEN1) led to CAG repeat expansion during base excision repair. Using biochemistry and cell biology approaches, we are now exploring the molecular mechanisms underlying CAG repeat instability induced by both endogenous and environmental oxidative DNA damage that involves base excision repair. We have discovered that CAG repeats were expanded through DNA slippage rather than Pol β strand-displacement synthesis during BER. This indicates that CAG repeats may be expanded more easily during DNA repair than DNA replication. In addition, we are studying how to inhibit the instability of trinucleotide repeat instability by manipulating cellular DNA base excision repair capacity during repair of oxidative DNA damage. The research is funded by NIH. Study on maintenance of epigenetic stability by DNA base excision repair DNA base damages that occur in CpG islands of tumor suppressor gene promoters were found to disrupt DNA methlyation pattern, a critical epigenetic marker that governs gene expression. Disruption of DNA methlyation pattern was found to suppress tumor suppressor gene expression that can further result in human cancer. We found that BER can effectively repair some base lesions on CpG islands that inhibit DNA methylation. We are now studying how individual BER enzymes and cofactors can effectively repair the DNA damages on CpG islands, thereby sustaining the stability of epigenetics on tumor suppressor genes and preventing cancer development. Study on DNA base excision repair of DNA damages on short tandem repeats (STR) and its application in forensic sciences DNA damages that occur on short tandem repeat genetic markers or loci could significantly compromise PCR amplification of DNA of forensic casework. Current work in forensic sciences focuses on development of new sensitive approach for improving amplification of DNA from degraded DNA of forensic casework. Since degraded DNA may bear a variety of DNA base lesions and single-strand DNA breaks that lead to the failure of PCR amplification of STR of degraded DNA, we are interested in studying how DNA base excision repair may efficiently repair the damages on STR and how the repair mechanism may improve the PCR amplification of STR of degraded DNA from forensic casework samples. The long-term research goals in my laboratory is to identify DNA base excision repair enzymes and cofactors as new targets for prevention, diagnosis and treatment of human diseases such as cancer, neurodegeneration and others as well as develop a new approach for improving detection of STR from degraded DNA of forensic casework samples by making use of base excision repair.