The DBHS proteins SFPQ, NONO and PSPC1: a multipurpose molecular scaffold

Abstract

Nuclear proteins are often given a concise title that captures their function, such as ‘transcription factor,’ ‘polymerase’ or ‘nuclear-receptor.’ However, for members of the Drosophila behavior/human splicing (DBHS) protein family, no such clean-cut title exists. DBHS proteins are frequently identified engaging in almost every step of gene regulation, including but not limited to, transcriptional regulation, RNA processing and transport, and DNA repair. Herein, we present a coherent picture of DBHS proteins, integrating recent structural insights on dimerization, nucleic acid binding modalities and oligomerization propensity with biological function. The emerging paradigm describes a family of dynamic proteins mediating a wide range of protein–protein and protein–nucleic acid interactions, on the whole acting as a multipurpose molecular scaffold. Overall, significant steps toward appreciating the role of DBHS proteins have been made, but we are only beginning to understand the complexity and broader importance of this family in cellular biology.

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

“…The DBHS family shares highly conserved tandem N-terminal RRMs, a NonA/paraspeckle domain (NOPS) and a C-terminal coiled-coil (93). SFPQ binds wide range of nucleic acids and can be found in the pre-assembled spliceosome complex.…”

“…SFPQ binds wide range of nucleic acids and can be found in the pre-assembled spliceosome complex. However, SFPQ is not an essential member of spliceosome, but rather act as a molecular scaffold and involve cotranslational and alternative splicing (93). Mutations in SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21 have been discovered in 10% of AML patients in a mutually exclusive manner (94).…”

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

“…They are predominantly defined by colocalization of dynamic and multifunctional RNA-binding proteins, such as splicing factor, proline-and glutamine-rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO) or paraspeckle component 1 (PSPC1). These factors belong to the Drosophila behavior/human splicing (DBHS) protein family that forms a dynamic scaffold with the long noncoding RNA NEAT1 (Bond and Fox, 2009;Clemson et al, 2009;Fox et al, 2005;Knott et al, 2016). The major function of paraspeckles is nuclear retention of mRNA that contains doublestranded (ds)RNA structures at the 3′ untranslated region (UTR), which are generally formed by adenosine-to-inosine edited inverted repeats (Fox and Lamond, 2010).…”

“…Besides being essential paraspeckle components, DBHS proteins act as molecular scaffolds that synergistically associate with a broad spectrum of transcription factors, DNA and RNA. This allows the scaffold to promote transcription initiation, elongation and termination, to facilitate co-transcriptional processing -in particular splicing -and to regulate mRNA transport and cytosolic trafficking (Knott et al, 2016). In addition, paraspeckles may mediate regulatory crosstalk with the nucleolus: paraspeckle proteins localize to perinucleolar caps when RNA Pol II transcription is inhibited, and it has been observed that PSPC1 shuttles between paraspeckles and nucleoli (Fox and Lamond, 2010).…”

“…1). Among them are the cytoplasmic RNP assemblies -stress granules (SGs) (Kedersha et al, 1999), processing bodies (PBs) (Eulalio et al, 2007a;Jain and Parker, 2013), GW-bodies (Eulalio et al, 2009;Stoecklin and Kedersha, 2013), germline P-granules (also known as P-bodies) (Brangwynne et al, 2009;Voronina et al, 2011), neuronal granules (Buchan, 2014), mitochondrial RNA granules (MRGs) (Antonicka and Shoubridge, 2015), as well as the nuclear RNP assemblies -nucleoli (Brangwynne et al, 2011;Mahboubi and Stochaj, 2014), nuclear pores (Frey et al, 2006), Cajal bodies (CBs) (Machyna et al, 2013;Staneǩ and Neugebauer, 2006), promyelocytic leukemia (PML) bodies, histone locus body (Nizami et al, 2010), splicing speckles, other nuclear speckles and paraspeckles (Fox and Lamond, 2010;Knott et al, 2016;Shevtsov and Dundr, 2011).…”