▪ Abstract Ubiquitous in eukaryotic cells, the La protein associates with the 3′ termini of many newly synthesized small RNAs. RNAs bound by the La protein include all nascent transcripts made by RNA polymerase III as well as certain small RNAs synthesized by other RNA polymerases. Recent genetic and biochemical analyses have revealed that binding by the La protein protects the 3′ ends of these RNAs from exonucleases. This La-mediated stabilization is required for the normal pathway of pre-tRNA maturation, facilitates assembly of small RNAs into functional RNA-protein complexes, and contributes to nuclear retention of certain small RNAs. Studies of mutant La proteins have given some insights into how the La protein specifically recognizes its RNA targets. However, many questions remain regarding the molecular mechanisms by which La protein binding influences multiple steps in small RNA biogenesis. This review focuses on the roles of the La protein in small RNA biogenesis and also discusses data that implicate the La protein in the translation of specific mRNAs.

Patients with systemic lupus erythematosus and other rheumatic diseases often possess autoantibodies directed against discrete classes of small ribonucleoprotein particles (RNPs). The class of particles recognized by anti-Ro antibodies contains from two to four small cytoplasmic RNAs, depending on the mammalian species examined. We find that an antigenic polypeptide of 60 kDa is the major protein residing in Ro RNPs from human HeLa cells. To determine what common feature of Ro RNA sequence or structure is recognized by the Ro protein, we carried out ribonuclease protection experiments on isolated Ro RNPs from HeLa cells. For each of the three human Ro RNAs whose sequence is known, the most highly protected portion found in immunoprecipitates corresponded to the lower section of a stem formed by base-pairing the 5' and 3' ends of the RNA. Within this protected helix is a highly conserved region composed of seven identical base pairs with a single bulged cytidine. We discuss possible functions for the Ro RNPs.

Small ribonucleic acid (RNA)-protein complexes precipitated by anti-Ro and anti-La antibodies from lupus patients have been examined with emphasis on their RNA components. In both ribonucleoprotein (RNP) classes, the numbers of different RNA molecules and their sequences vary between mouse and human cells. The complex mixtures of La RNAs include two previously sequenced 4.5S RNAs from mouse cells and 5S ribosomal RNA-like molecules from both mouse and human cells. All Ro and La RNAs possess 5-triphosphates. Some La RNAs have internal modifications typical of transfer RNAs. The Ro RNPs are quite stable and are localized by immunofluorescence in the cell cytoplasm, whereas the majority of the La RNPs turn over rapidly and reside in the nucleus. Despite these differences, reconstitution experiments show that the Ro particles carry the La as well as the Ro determinant. Studies using a nuclear transcription system demonstrate that most of the La RNAs are synthesized by RNA polymerase III. The possibility that the La protein(s) functions in the transcription or maturation of all RNA polymerase III transcripts is discussed.

Commensal bacterial orthologs of the human autoantigen Ro60 may trigger cross-reactive T and B cells that initiate and sustain chronic autoimmunity in lupus.

Damage to RNA from ultraviolet light, oxidation, chlorination, nitration, and akylation can include chemical modifications to nucleobases as well as RNA-RNA and RNA-protein crosslinking. In vitro studies have described a range of possible damage products, some of which are supported as physiologically relevant by in vivo observations in normal growth, stress conditions, or disease states. Damage to both messenger RNA and noncoding RNA may have functional consequences, and work has begun to elucidate the role of RNA turnover pathways and specific damage recognition pathways in clearing cells of these damaged RNAs.