Established and Evolving Roles of the Multifunctional Non-POU Domain-Containing Octamer-Binding Protein (NonO) and Splicing Factor Proline- and Glutamine-Rich (SFPQ)

Abstract

It has been more than three decades since the discovery of multifunctional factors, the Non-POU-Domain-Containing Octamer-Binding Protein, NonO, and the Splicing Factor Proline- and Glutamine-Rich, SFPQ. Some of their functions, including their participation in transcriptional and posttranscriptional regulation as well as their contribution to paraspeckle subnuclear body organization, have been well documented. In this review, we focus on several other established roles of NonO and SFPQ, including their participation in the cell cycle, nonhomologous end-joining (NHEJ), homologous recombination (HR), telomere stability, childhood birth defects and cancer. In each of these contexts, the absence or malfunction of either or both NonO and SFPQ leads to either genome instability, tumor development or mental impairment.

Keywords: ATR/ATM; DNA damage response; NonO/p54nrb; SFPQ/PSF; birth defects; cancer; cell cycle; checkpoint control.

Figure 1

DBHS family nomenclature. NonO has also been termed the 54 kDa Nuclear RNA-Binding Protein (p54nrb) and the 55 kDa Nuclear Matrix Protein (nmt55). SFPQ was originally named the PTB-associated splicing factor (PSF). NonO and SFPQ are two members of the DBHS family. The DBHS conserved regions contain two RNA recognition motifs (RRMs, in red), a NONA/ParaSpeckle (NOPS) domain (in purple) and a coiled coil region (in blue). SFPQ also contains an N-terminal Arginine Glycine (RGG) region (in pink) and an uncharacterized DNA-binding domain (DBD, in green) at the N-terminus of its DBHS region. NonO has a highly charged helix–turn–helix (HTH in blue) C-terminal to its DBHS region, which has been suggested to have DNA-binding activity [19,20,21,22,24].

Figure 2

Alignment of DBHS family proteins. (A) Structural elements of DBHS family proteins: NonO, SFPQ, PSPC1, NonA, hrp65 and NonO-1a. Their C-termini contain the conserved DBHS region (shown in green) consisting of (from N-terminus to C-terminus) RNA-binding domains (RRM1, 2), NONA/ParaSpeckle domains (NOPSs, not pictured) and coiled coil domains. Also pictured are positively/negatively charged residue regions (+/−, brown), HTH domains (blue) and NLS regions (yellow). (B). NonO, SFPQ and TFE3 chimeric proteins. Structural representations of the wild-type NonO, SFPQ and TFE3 (transcription factor binding to IGHM enhancer 3) chimeric proteins. The TFE3 protein contains acidic activation (AAD) and DNA-binding domains (bHLH; Z) and has an overall length of 575 amino acids. Scales in (A,B) are indicated with scale bars representing 100 amino acids (aa) at the lower right.

Figure 3

Various mutations across the human NONO locus are associated with birth defects. The top line shows, to scale, the coding (yellow) and noncoding (blue) exons of NONO located at Xq13.1. The numerals a–p denote the positions of pathologic point and/or deletion mutations within coding regions; q denotes the deletion of exons 1–3, which includes part of the 5′ noncoding region. Details of the various mutations and their clinical ramifications are provided in references [52,53,92,93,94,95].