Telomerase and TERRA: RNA machines at chromosome ends

Joachim Lingner is Full Professor for life sciences at the Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland. Lingner obtained his PhD (1992) at the Biozentrum of the University of Basel in the laboratory of Walter Keller studying the 3' end formation of messenger RNAs. During his postdoctoral work (1993-1997) with Thomas Cech at the Howard Hughes Medical Institute of the University of Colorado at Boulder, Lingner discovered the catalytic subunit of telomerase (TERT) which counteracts telomere shortening and cellular senescence in somatic and germline stem cells, and in cancer. Since 1997, Lingner is group leader at the Swiss Institute for Experimental Cancer Research (ISREC) and since 2005 professor at EPFL.

The Lingner lab studies how telomeres enable chromosome stability and how they are maintained to regulate cellular lifespan. The team elucidated how the telomerase enzyme is regulated at chromosome ends to counteract telomere shortening. The lab also discovered that telomeres are transcribed into long the long noncoding RNA TERRA, which regulates telomeric chromatin structure and telomere maintenance by telomerase and homology directed repair. Finally, the team developed techniques to purify telomeric chromatin and determine its protein composition by mass spectrometry uncovering changes that occur in the telomeric proteome during aging and in disease including cancer.

Lingner obtained a START-fellowship from the Swiss National Science Foundation (1997), the Friedrich Miescher prize (2002) and an ERC advanced investigator award (2008). He is an elected member of EMBO (2005) and the Academia Europaea (2020). 

About the Lecture

Telomeres are the nucleoprotein structures at the ends of eukaryotic chromosomes. Telomere length regulates cellular lifespan during development, aging and tumorigenesis. Telomeres shorten in differentiated human cells due to the end replication problem and the lack of telomerase. Short telomeres induce cellular senescence which limits the replicative potential of precancerous lesions. Telomerase consists of the telomerase reverse transcriptase (TERT) catalytic protein subunit and the noncoding telomerase RNA moiety (TR), which provides a template for the synthesis of the telomere repeats. While being repressed in most healthy somatic cells, telomerase is expressed in somatic and germline stem cells to counteract telomere shortening. Also, cancer cells must maintain telomeres for their unlimited growth. Thus, they either express telomerase, or they activated the so-called Alternative Lengthening of Telomeres (ALT) pathway. In ALT, telomeres are being elongated through DNA recombination in which truncated telomeres copy sequences from other telomeres. The ALT pathway is supported by high levels of the noncoding RNA TERRA, which is expressed at chromosome ends. Thus, not only telomerase (TR) but also ALT (TERRA) depends on a noncoding RNA.

In my lecture, I will discuss the composition and function of telomerase, and how it is regulated at chromosome ends. I will also introduce the discovery and function of TERRA, how it associates with telomeric DNA forming DNA:RNA hybrids, and how TERRA may engage the DNA recombination machinery for telomere elongation.