Research Interests
Research in our lab focuses on elucidating the molecular mechanisms for maintaining integrity of telomeres. The physical ends of eukaryotic chromosomes, telomeres, are special DNA-protein structures composed of double-stranded (TTAGGG)n repetitive DNA sequences and proteins associated with telomere DNA. Telomeres protect genome stability by preventing chromosomes from inappropriate fusions, degradation, and recombination. Failure of maintaining functional telomeres results in genome instability that leads to diseases such as cancer and premature aging.
In normal human somatic cells, telomeres ends lose short stretches of DNA each time a cell divides. After a number of cell divisions, telomeres become critically short, signaling cells to growth arrest. Telomere shortening is considered as one of the causal mechanisms for cellular aging. Cancer cells bypass this telomere shortening induced growth arrest to achieve their unlimited growth capacity. Most cancer cells turn on a special enzyme called telomerase to add (TTAGGG)n repeats to short telomeres, therefore maintaining telomere length.
While earlier studies have revealed the importance of telomere length maintenance, recent studies have found that maintaining stable telomere structures is essential for the long-term cell growth. The ends of telomere DNA, if exposed, would be recognized as natural DNA breaks and would be attacked by DNA repair machinery, leading to genome instability. To prevent exposure of telomere ends, telomeres form special nucleoprotein structures, t-loops. If this protective structure is disrupted, telomere DNA will be recognized as damaged DNA. The consequence of DNA repair activities at telomeres is genome instability such as chromosome end-to-end fusions and chromosome breakage during mitosis. These drastic outcomes then trigger cellular senescence or apoptosis, therefore inhibiting cell growth.
The protective telomere structure is maintained by numerous proteins associated with telomeres, among which are those involved in DNA repair, replication, and recombination. The long-term goal of our research is to characterize the functions of DNA replication and repair factors at telomeres, and how the network of these proteins interacts with telomere DNA and telomerase to maintain telomere integrity. In particular, we focus on two areas: 1) to define the molecular mechanism for t-loop formation and the roles of DNA repair factors in telomere structure protection, and 2) to determine the role of DNA replication proteins in regulating telomerase-mediated telomere elongation in cancer cells. Our studies will lead to new avenues of cancer therapy and premature aging.
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