Identifying the Surfaces of Human Protein TPP1 and Telomerase RNA that Interact with One Another to Improve Enzyme Function and Association at the Telomere

Bell, Caitlin

Undergraduate Honors Thesis

Identifying the Surfaces of Human Protein TPP1 and Telomerase RNA that Interact with One Another to Improve Enzyme Function and Association at the Telomere Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/0k225b48r

Abstract

Telomerase is a cellular reverse transcriptase that adds tracts of telomeric DNA to the ends of linear chromosomes as a means of solving the end replication problem, preventing nonhomologous end joining, and eliminating inappropriate DNA damage response. In humans, the G-rich telomeric repeats are bound in a sequence-specific manner by proteins belonging to the shelterin complex. Two of the proteins incorporated in the shelterin complex are POT1 and TPP1. POT1 binds to the single stranded telomeric overhang with high affinity and specificity, and TPP1 forms a complex with POT1 to increase POT1-DNA affinity. The POT1-TPP1 complex has been found to participate in a dual role at the chromosome end, both protecting the integrity of the telomere and engaging in telomerase stimulation. Oligonucleotide/oligosaccharide binding folds (OB domains) consist of a five-stranded closed beta barrel, and most OB-folds use this folded face for ligand binding or as an active site. The DNA-binding domain of POT1 is composed of two tandem N-terminal OB domains. Interestingly, the N-terminal OB-fold of TPP1 (TPP1-OB) is the domain implicated in the actual act of recruiting telomerase to the telomere via interaction with the telomerase RNA and/or TERT protein; this interaction could be direct or indirect. The goal of this work was to elucidate what surface of TPP1-OB is responsible for the recruitment interaction with telomerase, and then to examine what element, if any, in the telomerase RNA subunit is interacting with TPP1. Studying the mechanisms of telomerase access to the telomere is essential for understanding normal biological processes, like aging, as well as comprehending the mechanistic cause of diseases like aplastic anemia, dyskeratosis congenita, cancer, and idiopathic pulmonary fibrosis.

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