University Distinguished Professor
Professor | Biochemistry & Biophysics, Genetics
telomerase, telomere, Arabidopsis, chromosome, ribonucleoprotein
Telomeres cap the ends of eukaryotic chromosomes and play essential roles in conferring genome stability. The critical function of telomeres was demonstrated in plants 80 years ago by the pioneering work of Barbara McClintock. A half-century later, our lab developed Arabidopsis thaliana as a powerful comparative model for elucidating fundamental aspects of telomere biology. Our research employs biochemical, genetic, genomic, proteomic, and molecular evolution strategies to elucidate the origin and function of telomere-related proteins and RNAs using the flowering plant Arabidopsis as a model system.
Telomere biology in plants
The stability of eukaryotic genomes derives in part from telomeres, the nucleoprotein caps on chromosome termini. Telomeric DNA is maintained by telomerase, a reverse transcriptase that continually replenishes telomeric DNA using a catalyst TERT and an integral long noncoding RNA, TR, as a template. Mis-regulation of telomerase is linked to stem cell disease and tumorigenesis in humans. Our work has revealed that plants are much more tolerant of genome instability, particularly telomere dysfunction than mammals. The major thrust of our research is to provide a deeper understanding of the evolution and regulation of telomere-related factors and their mechanisms for safeguarding genome integrity.
Telomerase structure and evolution
The integrity of eukaryotic genomes derives in part from telomeres, the nucleoprotein caps on chromosome ends. The telomerase reverse transcriptase maintains telomeric DNA, a ribonucleoprotein complex that continually replenishes telomeric DNA using a catalyst TERT and an integral long noncoding RNA, TR, as a template. Mis-regulation of telomerase is linked to stem cell disease and tumorigenesis in humans. The predominant structure models for telomerase derive human and Tetrahymena telomerases. We recently identified TR from A. thaliana and, working with collaborators from Arizona State University, developed a robust secondary structure model for plant TR that provided an evolutionary bridge for the highly divergent TR molecules studied to date. TERT and TR are common to all telomerases, but the accessory subunits of the enzyme complex are unique to each particle. A current focus in the lab is the comprehensive identification of telomerase-associated factors and the acquisition of a 3D structure for plant telomerases to uncover both novel mechanisms and unifying principles for this essential enzyme.
J. Song, D. Logeswaran, C. Castillo-Gonzalez, Y. Li, S. Bose, B. B. Aklilu, Z. Ma, A. Polkhovskiy, J. J. Chen, D. E. Shippen, The conserved structure of plant telomerase RNA provides the missing link for an evolutionary pathway from ciliates to humans. Proc. Natl. Acad. Sci. USA 116, 24542–24550 (2019).
Defining extra-nuclear functions for telomere proteins
Telomeres have been heralded as both a sentinel and elicitor of physiological stress, but recent studies indicate that telomere-related proteins are also regulated by, and engage, the oxidative stress response machinery in the cytoplasm. We are investigating noncanonical functions of TERT, and Protection of Telomeres 1, an essential telomere end-binding protein. POT1 is among the most highly conserved members of the telomere capping complex and a prominent target for mutations in cancers. We discovered that only one of the two Arabidopsis POT1 paralogs are required for telomere maintenance. Hence, comparative analysis of the two POT1 genes in A. thaliana affords a unique opportunity to uncover the full complement of POT1 functionality. We are currently studying the intracellular trafficking of POT1 proteins, defining their interaction partners, and investigating how their cytoplasmic activities impact chromosome condensation and integrity.
B. Barbero Barcenilla and D. E. Shippen, Back to the future: The intimate and evolving connection between telomere-related factors and genotoxic stress. J. Biol. Chem. 294, 14803–14813 (2019).
To Academic Professional Track Faculty