The Ro Autoantigen Binds Misfolded U2 Small Nuclear RNAs and Assists Mammalian Cell Survival after UV Irradiation

Abstract

The Ro 60 kDa autoantigen, an RNA binding protein, is a major target of the immune response in patients with systemic lupus erythematosus. As mice lacking Ro develop a lupus-like syndrome, Ro may be important for preventing autoimmunity. However, the cellular function of Ro, which binds small cytoplasmic RNAs of unknown function called Y RNAs, has been enigmatic. Ro has been proposed to function in 5S rRNA quality control based on experiments in Xenopus laevis oocytes, and a Ro ortholog enhances survival of the eubacterium Deinococcus radiodurans after ultraviolet irradiation. To test the general importance of these two observations for Ro function, we investigated the role of Ro in mammalian cells. We report that, in mouse embryonic stem (ES) cells, Ro binds variant spliceosomal U2 snRNAs. Expression of mouse U2 snRNAs in Xenopus oocytes reveals that binding occurs in nuclei and appears to involve recognition of misfolded RNA. Moreover, mouse ES cells lacking Ro exhibit decreased survival after ultraviolet irradiation. In irradiated cells, both Ro and a Y RNA accumulate in nuclei. We propose that Ro plays a general role in small RNA quality control and that this function is important for cell survival after ultraviolet irradiation.

PARN Modulates Y RNA Stability and Its 3′-End Formation

“…First, PARN patient cells have a defective response to UV irradiation stress compared to controls (52). Y RNAs, in complex with the Ro protein, accumulate in the nucleus upon UV stress as part of the cell's DNA damage response mechanism, suggesting an important function in adaptation to UV stress (53,54). Therefore, PARN deficiency could negatively impact the cell's DNA damage response mechanism.…”

C1q: Its Functions within the Innate and Adaptive Immune Responses and its Role in Lupus Autoimmunity

“…could possibly interfere with a physiologic function of this molecule in the protection against deleterious effects of ultraviolet light. (O'Brien and Wolin 1994;Chen et al, 2003).…”

Nucleic acid-associated autoantigens: Pathogenic involvement and therapeutic potential

“…As the binding sites for La are the RNA's terminal uridylate residues that are normally removed during maturation of RNAs, La binds normally RNA precursors rather than mature RNAs. The exact biological role of Ro60 has still not been fully elucidated, but it has been suggested that Ro60 binds misfolded, defective noncoding RNAs that are eventually degraded, thus working in a quality control system that marks damaged RNAs for decay [252,253] Ro60 seems also to play a role in cellular resistance to UV irradiation [254], probably by being involved in the degradation of damaged RNAs following UV irradiation.…”