ABSTRACT
Long noncoding RNAs (lncRNAs) have emerged as regulators of diverse biological processes. Here, we describe the initial functional analysis of a poorly characterized human lncRNA (LINC00657) that is induced after DNA damage, which we termed "noncoding RNA activated by DNA damage", or NORAD. NORAD is highly conserved and abundant, with expression levels of approximately 500-1,000 copies per cell. Remarkably, inactivation of NORAD triggers dramatic aneuploidy in previously karyotypically stable cell lines. NORAD maintains genomic stability by sequestering PUMILIO proteins, which repress the stability and translation of mRNAs to which they bind. In the absence of NORAD, PUMILIO proteins drive chromosomal instability by hyperactively repressing mitotic, DNA repair, and DNA replication factors. These findings introduce a mechanism that regulates the activity of a deeply conserved and highly dosage-sensitive family of RNA binding proteins and reveal unanticipated roles for a lncRNA and PUMILIO proteins in the maintenance of genomic stability.
Subject(s)
Genomic Instability , RNA, Long Noncoding/metabolism , RNA-Binding Proteins/metabolism , Animals , Base Sequence , Chromosomal Instability , HCT116 Cells , Humans , Mice , Ploidies , RNA, Long Noncoding/chemistry , RNA, Long Noncoding/geneticsABSTRACT
The release of nascent RNA from transcribing RNA polymerase complexes is required for all further functions carried out by RNA molecules. The elements and processing machinery involved in 3' end formation therefore represent key determinants in the biogenesis and accumulation of cellular RNA. While these factors have been well-characterized for messenger RNA, recent work has elucidated analogous pathways for the 3' end formation of other important cellular RNA. Here, we discuss four specific cases of non-mRNA 3' end formation-metazoan small nuclear RNA, Saccharomyces cerevisiae small nuclear RNA, Schizosaccharomyces pombe telomerase RNA, and the mammalian MALAT1 large noncoding RNA-as models of alternative mechanisms to generate RNA 3' ends. Comparison of these disparate processing pathways reveals an emerging theme of evolutionary ingenuity. In some instances, evidence for the creation of a dedicated processing complex exists; while in others, components are utilized from the existing RNA processing machinery and modified to custom fit the unique needs of the RNA substrate. Regardless of the details of how non-mRNA 3' ends are formed, the lengths to which biological systems will go to release nascent transcripts from their DNA templates are fundamental for cell survival.
