Defining extra-nuclear functions for telomere proteins  

Telomeres have been heralded as a 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 mutation in cancers.  We discovered that only one of the two the Arabidopsis POT1 paralogs is required for telomere maintenance. Hence, comparative analysis of the two POT1 genes in A. thalianaaffords 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.    

Diversification of telomere protein function. PROTECTION OF TELOMERES 1 (POT1) proteins participate in numerous facets of DNA metabolism in addition to conventional telomere biology. Several POT1 proteins accumulate in the cytoplasm.  The function of cytoplasmic telomere-related proteins is not understood, but appears to be related to the stress response. Shown are A. thaliana POT1a (AtPOT1a) and POT1b (AtPOT1b); C. elegans POT1 proteins CeOB1, CeOB2 and MRT1; human POT1 (hPOT1) and its splice variants; mouse POT1a (mPOT1a) and POT1b (mPOT1b); and T. thermophila POT1 (TtPOT1) and POT2 (TtPOT2).  See JBC 294(40): 14803-14813.

Barbero Barcenilla, B. and D.E. Shippen (2019) Back to the future: The intimate and evolving connection between telomere-related factors and genotoxic stress.  J. Biol. Chem. 294(40): 14803-14813.