Project Summary/Abstract RNA quality control pathways play essential roles in ridding cells of defective RNAs that arise from RNA damage, misprocessing, or transcription of pseudogenes. Much has been learned over the past decades about the quality control pathways that monitor the integrity of protein-coding messenger (m)RNAs, such as the nonsense-mediated mRNA decay pathway. Much less is known about those quality control pathways that monitor non-coding (nc)RNAs, which make up ≈95% of the cell's RNA and are susceptible to the same types of damage as mRNAs. The primary goal of this research is to uncover the mechanisms whereby ncRNA quality control pathways distinguish normal from defective RNAs, how the defective RNAs are targeted for degradation, and what are the consequence of failures in these pathways to cell function and human health. To address these questions we will over the next five years focus on the quality control of abundant human stable small ncRNAs that are critical to cell function, including small nuclear (sn)RNAs of the spliceosome and 7SL RNA of the signal recognition particle. We will take advantage of the fact that 1,000s of pseudogenes of these RNAs exist in the human genome, many of which produce defective ncRNA variants that must be detected and degraded by quality control pathways. The features of these defective ncRNAs that are identified by quality control pathways and the factors involved in their degradation will be uncovered through targeted and global assays monitoring effects of degradation factor depletion and ncRNA mutagenesis on the stability of the ncRNA variants. We recently uncovered a central role for 3' end-processing machineries in one such quality control pathway that targets defective snRNAs, and will therefore additionally over the next five years pursue RNA targets and potential roles in RNA quality control of 3' end processing factors, including factors that when defective cause human neurodegenerative disorders. These efforts should uncover principles by which defective human small ncRNAs are detected and degraded by quality control pathways, a mostly unexplored yet critical aspect of gene expression. These efforts also have the potential to provide insights into defects in RNA processing that lead to human disease such as neurodegenerative disorders.