Conserved mechanism of protein-RNA recognition in telomerase

Telomeres, the ends of linear eukaryotic chromosomes, are highly specialized structures that are essential for genome integrity and stability. In most eukaryotes telomere length is replenished by telomerase, a specialized reverse transcriptase that iteratively adds telomeric repeats at the chromosome ends. Telomerase activity and telomere length are closely related to organismal aging and tumorigenesis, and telomerase dysfunction can cause several human premature aging syndromes, such as dyskeratosis congenital and aplastic anemia. Telomerase is a large ribonucleoprotein complex minimally composed of a catalytic telomerase reverse transcriptase (TERT) and an RNA component (TR) that provides the template for telomeric DNA synthesis. Two conserved domains of vertebrate TR, the template-pseudoknot (T/PK) and conserved regions 4 and 5 (CR4/5), bind toTERT independently, and are sufficient to reconstitute telomerase activity in trans with TERT. However, the molecular mechanism of how TERT and TR assemble into a functional telomerase complex remains unclear.

HUANG Jing and her colleagues from a research group led by Prof. LEI Ming at National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, determined the crystal structure of CR4/5 complexed with TRBD in which CR4/5 adopts an L-shaped three-way junction conformation with its two arms clamping onto TRBD. Both sequence and the conformation of CR4/5 are required for the interaction. The structural and mutational analyses strongly suggests that the observed CR4/5-TRBD interaction is common to species from yeast to humans, and CR4/5 in vertebrate TR might play a similar role in telomerase regulation as stem-loop IV in Tetrahymena TR. The high-resolution map of telomerase RNA-protein binding interface would offer new opportunities for the development of therapeutics that modulate telomerase activity for the treatment of human diseases.

This study entitled “Structural basis for protein-RNA recognition in telomerase” was published online in Nature Structural and molecular biology on May 4, 2014.This work was done in collaboration with Prof. CHEN Julian from Arizona State University, and supported by grants from the Ministry of Science and Technology of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, and the US National Institutes of Health.

Model for the protein-RNA recognition in telomerase. (Image provided by Prof. LEI Ming’s group)