Abstract
The Nrd1–Nab3–Sen1 (NNS) complex integrates molecular cues to direct termination of noncoding transcription in budding yeast. NNS is positively regulated by histone methylation as well as through Nrd1 binding to the initiating form of RNA PolII. These cues collaborate with Nrd1 and Nab3 binding to target RNA sequences in nascent transcripts through their RRM RNA recognition motifs. In this study, we identify nine lysine residues distributed amongst Nrd1, Nab3 and Sen1 that are methylated, suggesting novel molecular inputs for NNS regulation. We identify mono-methylation of one these residues (Nab3-K363me1) as being partly dependent on the H3K4 methyltransferase, Set1, a known regulator of NNS function. Moreover, the accumulation of Nab3-K363me1 is essentially abolished in strains lacking SET3, a SET domain containing protein that is positively regulated by H3K4 methylation. Nab3-K363 resides within its RRM and physically contacts target RNA. Mutation of Nab3-K363 to arginine (Nab3-K363R) decreases RNA binding of the Nab3 RRM in vitro and causes transcription termination defects and slow growth. These findings identify SET3 as a potential contextual regulator of Nab3 function through its role in methylation of Nab3-K363. Consistent with this hypothesis, we report that SET3 exhibits genetic activation of NAB3 that is observed in a sensitized context.
Highlights
RNA PolII transcriptional termination is controlled through two distinct mechanisms in the budding yeast Saccharomyces cerevisiae [1,2,3,4]
Protein lysine methylation is most prominently understood through studies of histone methylation, this modification has emerged as a Post-translational modifications (PTMs) that impacts a wide array of proteins [60]
We identify here nine methylated lysine residues in the NNS transcriptional termination complex and show that one of these residues, Nab3-K363, is of critical importance for NNS function through its role in mediating RNA binding
Summary
RNA PolII transcriptional termination is controlled through two distinct mechanisms in the budding yeast Saccharomyces cerevisiae [1,2,3,4]. Genetic evidence suggests that NNS is positively regulated through methylation of histone H3 on lysine-4 (H3K4me), a chromatin mark widely associated with transcriptional initiation and deposited by the conserved Set protein [23,24,25,26,27,28,29,30]. By integrating these signals together with Nrd and Nab binding to cognate RNA sequences, NNS is thought to dislodge PolII from DNA in a manner that employs Sen ATPase activity [31,32,33,34]
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