Negative Regulation of Telomerase In Arabidopsis
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Intellectual Merit. Telomeres are the physical ends of chromosomes and they are synthesized and maintained by a specialized ribonucleoprotein (RNP) enzyme called telomerase. Telomerase activity is required to fully replicate the chromosome terminus and to distinguish it from damaged DNA. The prolonged absence of telomerase leads to end-to-end chromosome fusions. Thus, telomerase is essential to sustain genome integrity. On the other hand, inappropriate action of telomerase at internal double-strand breaks in the DNA can be catastrophic if telomeres form inappropriately to cause gene loss. Consequently, telomerase activity must be highly regulated and confined to the tips of natural chromosome ends. Much research has focused on understanding how telomerase is recruited and activated at telomeres, but little is known about mechanisms of negative regulation. The overall goal of this research is to examine mechanisms that suppress telomerase function in the model plant Arabidopsis. Preliminary studies from the Shippen lab reveal a complex and novel regulatory pathway for Arabidopsis telomerase that involves multiple telomerase enzymes composed of different protein subunits and different telomerase RNA (TER) subunits. The TER1 RNP is a positive regulator of telomerase, and like its counterparts in yeast and vertebrates, it is required to maintain telomeres in vivo. In contrast, the TER2 RNP is a novel negative regulator of telomerase activity and telomere maintenance. TER2 is spliced to form TER2s, whose function is unknown. Objective 1 will examine the biogenesis and function of TER2s. Objective 2 will study the dynamics of the TER2 RNP during the cell cycle to understand why this RNP cannot productively engage the chromosome terminus. Objective 3 will exploit a highly efficient new telomere formation assay to study how telomerase action is restricted at internal chromosome breaks. The results of this research will deepen understanding of how telomerase interaction with chromosomes is regulated to promote genome stability. Broader Impacts. In addition to shedding new light on fundamental mechanisms that promote chromosome integrity, the broader impact of this work is that it will provide research opportunities for a postdoctoral fellow and two graduate students in plant molecular biology and biochemistry, allowing them to work at the forefront of genome research. The current NSF study will also provide research opportunities for undergraduate students from Texas A&M and the University of Houston-Downtown, a URM campus. Throughout her career, Dr. Shippen has given numerous lectures for high school students and teachers, and undergraduate and graduate student organizations, including the Texas A&M University Women in Science and Engineering Ethel Ashworth-Tsutsui Memorial Lecture. Dr. Shippen has a long-standing interest in laboratory management. In 2002 she was an Instructor for the Burroughs Wellcome Fund/Howard Hughes Medical Institute Laboratory Management Course. In 2008-2009, Dr. Shippen was on sabbatical leave at Harvard University, where she worked on an NSF-funded project to define best practices in laboratory management. This study is ongoing and has already led to the development of a new graduate course on building scientific relationships and a mentoring program for postdocs and young PIs that provides practical solutions to common problems faced in guiding a research team. All the members of the Shippen lab benefit from this lab management research to develop leadership skills and shared responsibility for the scientific development of their colleagues.
