Telomeres are specialized structures at the end of chromosomes and essential to preserve our DNA that contain genetic information. Telomere shortening and dysfunction are known to accompany human aging. It is also known that patients with premature aging syndromes have abnormally short telomeres. Therefore, our long term goal is to understand how our cells protect telomeres from abnormal shortening to prevent untimely death. Recently, we have shown that two proteins, Timeless and Tipin, form a complex to function as a protector of DNA replication forks, the actual site of DNA synthesis. Our investigations have revealed that in the absence of Timeless or Tipin, replication forks collapse, leading to accumulation of broken chromosomes. Interestingly, yeast species also contain similar proteins to Timeless and Tipin, and their absence causes telomere shortening in yeast cells. Because of significant similarities in telomere maintenance mechanisms between yeast and humans, it is straightforward to suggest that human Timeless and Tipin also control telomere length by regulating replication of telomeres. Therefore, to further understand the mechanism of telomere DNA replication, this application proposes to investigate the roles of Timeless and Tipin in human telomere maintenance mechanism. First, we will determine whether Timeless and Tipin are required for proper length control of human telomeres using mammalian tissue cultured cells. Then, we will investigate how Timeless and Tipin contribute to the efficient replication of telomeric DNA. Since Timeless-Tipin is know to be involved in the DNA damage response that is governed by ATR protein kinase, and ATR is known to be involved in telomere length control, we will also investigate the role of Timeless-Tipin in ATR-dependent telomere maintenance mechanism. This research will determine how Timeless-Tipin promotes efficient replication of telomere DNA to protect the ends of chromosomes. Successful completion of this project will significantly enhance our knowledge of how telomeres are regulated to protect our chromosomes, thereby contributing to the understanding of aging mechanisms.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F08-F (20))
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Drexel University
Schools of Medicine
United States
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Leman, Adam R; Noguchi, Eishi (2014) Chromatin immunoprecipitation to investigate origin association of replication factors in mammalian cells. Methods Mol Biol 1170:539-47
Leman, Adam R; Noguchi, Eishi (2014) Linking chromosome duplication and segregation via sister chromatid cohesion. Methods Mol Biol 1170:75-98
Leman, Adam R; Noguchi, Eishi (2013) The replication fork: understanding the eukaryotic replication machinery and the challenges to genome duplication. Genes (Basel) 4:1-32
Leman, Adam R; Dheekollu, Jayaraju; Deng, Zhong et al. (2012) Timeless preserves telomere length by promoting efficient DNA replication through human telomeres. Cell Cycle 11:2337-47
Leman, Adam R; Noguchi, Eishi (2012) Local and global functions of Timeless and Tipin in replication fork protection. Cell Cycle 11:3945-55