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Telomere Dynamics and Genome Function

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International Research Program

Telomere Dynamics and Genome Function:
From DNA to Nucleosomes to Chromosomes

The Telomere Dynamics Group (TDG) is a multidisciplinary NTU/NUS team under Lead PI Prof. Daniela Rhodes that recently secured a S$ 24 million Tier 3 grant from the Ministry of Education to conduct groundbreaking telomere biology research on how human cells prevent aging and become immortal. Since cancer cells are also able to enjoy eternal life, understanding these processes will ultimately pave the way to find cures for cancer.

Our program focuses on the regulation of chromatin structure at mammalian telomeres. Whilst functional studies have identified multiple mechanisms that critically impact telomere function and how telomere defects lead to genome instability, key information on the unique underlying structural and dynamic properties of telomere chromatin is lacking. Our central aim is to provide an understanding at the molecular level of the multiple mechanisms that regulate telomere chromatin structure, dynamics , and stability , thus leading to novel insights into the biology of telomeres. Our ultimate aim is to apply this knowledge to address telomere malfunctioning in human aging and cancer.

Mammalian telomeres consist of highly conserved G-rich nucleotide repeats. They act as a platform for the recruitment of telomere-specific DNA binding factors as well as other telomere-binding proteins. Together, they form a protective cap on linear eukaryotic chromosomes. In addition, telomeric DNA is packaged by histones. A wealth of information exists on the functional role of specific proteins that bind at telomeres, but very little is known about telomeric chromatin and its interface with telomere-specific binding factors and further, how this specialized chromatin may differ in structure and dynamics from chromatin at internal chromosome sites.

Telomeres are biologically and medically very important. They protect the ends of eukaryotic chromosomes from inappropriate DNA repair and degradation. They control terminal replication of chromosomal DNA and localize chromosome ends within the nuclear space. Telomeres also provide a paradigm for gene silencing and are enriched in epigenetic marks characteristic of heterochromatin. Loss of such marks leads to telomere length defects that are a hallmark of cancer development and aging. Furthermore, very little is known about telomeric chromatin structure and its dynamics imparted by a combination of the repeated G-rich composition of telomeric DNA, specific telomere-binding factors and a set of repressive epigenetic marks enriched at telomeres. This is particularly true for structural changes that are likely to occur during the cell cycle to permit DNA replication, transcription, and chromosome segregation. Finally, telomeres through their specific composition and demarcated location at the tips of chromosomes, can be visualized in vivo using fluorescent probes. With significant improvements in imaging resolution, it should now be possible to begin to correlate in vitro with in vivo analyses of chromatin functional and structural states. Our proposed parallel in vitro and in vivo studies of the same chromosome domain is particularly powerful as it enables us to formulate and address specific questions arising from results of in vitro analyses and vice versa. The successful creation of such a network of scientific interests and technical expertise is therefore unique in the world.