EXPLORING RNA-PROCESSING PROTEINS AT THE TELOMERE -
DESCRIPTION (provided by applicant): The goals of this proposal are to examine how specific proteins interact with telomeres and/or components of the telomerase enzyme and to understand how these interactions are relevant to telomere dynamics. Telomerase is an enzyme complex that contains several key proteins as well as an RNA template that extends telomere ends and compensates for the inability of DNA replication to go to completion. Some proteins involved in RNA processing, therefore, may also directly and indirectly participate in telomerase RNA maturation and enzyme assembly. Mammalian nucleolin is a nucleolar protein involved in rRNA transcription and maturation, ribosome assembly, and nucleoplasmic transport. Budding yeast Nsr1p and nucleolin share structural similarities. The N-terminal half of both proteins contains lysine- and serine-rich regions which interact with topoisomerase I. The C-terminal half contains RNA-recognition motifs (RRM) and arginine/glycine rich domains (RGG boxes) important for RNA interaction. Via these C-terminal regions, both proteins bind guanine-rich oligonucleotides like those found in telomeres; additionally, nucleolin interacts with telomerase. We have observed that the deletion of NSR1 accelerates the senescence of telomerase-null cells indicating a role for Nsr1p at telomeres. The N-terminal half of nucleolin/Nsr1p also shares structural and functional similarities with mammalian heterogeneous nuclear ribonucleoprotein (hnRNP) A1. The closest homologue to hnRNP A1 in yeast is Npl3p; both proteins process mRNA. hnRNP A1 associates with telomere ends and stimulates telomerase activity; it is not known if Npl3p has a role at telomeres. This proposal aims to gain insight into how RNA-processing proteins are involved in telomere maintenance by exploring the functions of Nsr1p and Npl3p in budding yeast. Studying the dynamics of telomeres, how they are maintained, and their regulation by various factors has contributed significantly to understanding the natural processes of aging and cancer.
PUBLIC HEALTH RELEVANCE: Chromosome ends (or telomeres) shorten over time in many human cells; this shortening plays a role in the natural processes of aging, or the inappropriate re-lengthening is involved in cancer cell survival. Cells must, therefore, be able to preserve proper telomere function. This proposal seeks to understand how two particular RNA-processing proteins are able to maintain telomeres using baker's yeast as a comparative model system, thereby gaining insight into aging and cancer biology.
