Keeping the balance: The noncoding RNA 7SK as a master regulator for neuron development and function

Abstract

The noncoding RNA 7SK is a critical regulator of transcription by adjusting the activity of the kinase complex P-TEFb. Release of P-TEFb from 7SK stimulates transcription at many genes by promoting productive elongation. Conversely, P-TEFb sequestration by 7SK inhibits transcription. Recent studies have shown that 7SK functions are particularly important for neuron development and maintenance and it can thus be hypothesized that 7SK is at the center of many signaling pathways contributing to neuron function. 7SK activates neuronal gene expression programs that are key for terminal differentiation of neurons. Proteomics studies revealed a complex protein interactome of 7SK that includes several RNA-binding proteins. Some of these novel 7SK subcomplexes exert non-canonical cytosolic functions in neurons by regulating axonal mRNA transport and fine-tuning spliceosome production in response to transcription alterations. Thus, a picture emerges according to which 7SK acts as a multi-functional RNA scaffold that is integral for neuron homeostasis. K E Y W O R D S7SK, heterogeneous nuclear ribonucleoprotein (hnRNP), positive transcription elongation factor b (P-TEFb), survival motor neuron (SMN) This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Progress in 7SK ribonucleoprotein structural biology

“…Together 7SK RNA, MePCE, and Larp7 comprise the constitutively assembled ternary complex, called the 7SK core RNP (Figure 2), that is resistant to exonucleases, proteases, and high salt concentrations (Xue et al, 2010). To this 7SK core RNP, assembly of numerous accessory proteins guides discrete mechanisms of transcription regulation (Quaresma et al, 2016;Briese and Sendtner, 2021) (Table 1). The most wellestablished 7SK RNP function is its role in P-TEFb regulation.…”

“…This complexity challenges a detailed understanding of the structural basis for transcriptional regulation. Several excellent reviews discuss 7SK RNP functions and mechanisms in gene expression regulation ( Peterlin et al, 2012 ; McNamara et al, 2016a ; Briese and Sendtner, 2021 ; Studniarek et al, 2021 ; Fujinaga et al, 2022 ). Here, we describe progress in 7SK RNP structural biology, discuss outstanding challenges, and present perspectives for the future.…”

hnRNP R negatively regulates transcription by modulating the association of P‐TEFb with 7SK and BRD4

“…Whereas P‐TEFb binding to 7SK requires stem‐loop 1 and 4 (Egloff et al , 2006), hnRNPs interact with stem‐loop 3 of 7SK (Van Herreweghe et al , 2007; Briese et al , 2018). Importantly, binding of P‐TEFb and hnRNPs to 7SK is mutually exclusive and can be shifted towards one or the other depending on the transcriptional requirements (Briese & Sendtner, 2021). When nascent RNA levels are lowered by transcriptional inhibition, hnRNPs binding to 7SK is enhanced, causing the release of P‐TEFb from 7SK for transcription re‐activation.…”

C-terminal determinants for RNA binding motif 7 protein stability and RNA recognition

“…Together, these components minimally constitute the P-TEFb-inactivated 7SK RNP [16,23,24]. Numerous accessory proteins have been reported to promote release of P-TEFb from 7SK RNP [5,[25][26][27][28][29][30][31][32][33][34]. On release P-TEFb, Bromodomain 4 (Brd4), and other transcription factors trigger the transition of Pol II from a promoter-proximal paused to a processive elongation state [5,35,36].…”