Role of RNA Silencing in Telomere Dynamics

Xie, Zhixin

Abstract

RNA silencing, also known as RNA interference (RNAi), is a recent milestone discovery in molecular biology. A hallmark of RNA silencing is the generation of small RNAs of 20-~24-nucleotide in length, which function as essential regulators in most eukaryotes. Telomeres are protective structures formed as DNA-protein complexes at the ends of linear eukaryotic chromosomes. Telomeric DNAs typically consist of tandem arrays of short repeat sequences with the characteristic single-stranded G-rich 3'overhang. Telomeres are essential for the complete replication of chromosomes during cell division and prevent the chromosome ends from nucleolytic degradation and end-to-end fusion. Proper telomere maintenance is therefore crucial for genome integrity and cellular longevity. Defective telomere maintenance has been implicated in human diseases such as dyskeratosis congenita and cancer. Interestingly, a growing body of evidence from diverse models suggested a potential role of RNA silencing in telomere dynamics. In an effort to explore this possibility, we have identified a telomeric repeat-associated small interfering RNA species (tel-siRNAs) that has been conserved in a wide range of plant species, raising the possibility for a hidden link between RNA silencing and telomere dynamics in eukaryotes. Using a combination of genetic and biochemical approaches, the role of RNA silencing in telomere dynamics will be investigated. First, the genomic origin and biogenesis mechanism of the tel- siRNAs will be studied;second, the role of tel-siRNAs in telomere dynamics will be examined using the tel-siRNA-deficient mutants;and third, the tel-siRNA-associted effector complex will be characterized.

Public Health Relevance

Role of RNA Silencing in Telomere Dynamics Project Narrative Telomeres and their proper maintenance have long become one of the central themes in both aging and cancer biology. The proposed research promises to provide a better understanding of the molecular mechanisms underlying the maintenance of genome integrity in eukaryotes. The project is therefore highly relevant to human health.