ABSTRACT Demixing of proteins and nucleic acids into condensed liquid phases is rapidly emerging as a ubiquitous mechanism governing the organisation of molecules within the cell. Long disordered low complexity regions (LCRs) are a common feature of proteins that form biomolecular condensates. RNA-binding proteins with prion-like composition have been highlighted as drivers of liquid demixing to form condensates such as nucleoli, paraspeckles and stress granules. Splicing factor proline- and glutamine-rich (SFPQ) is an RNA- and DNA-binding protein essential for DNA repair and paraspeckle formation. Here, we show that the shorter C-terminal LCR of SFPQ is the main region responsible for the condensation of SFPQ in vitro and in the cell. In contrast, we find that, unexpectedly, the longer N-terminal prion-like LCR of SFPQ attenuates condensation, suggesting a more regulatory role in preventing aberrant condensate formation in the cell. Our data add nuance to the emerging understanding of biomolecular condensate formation, by providing the first example of a common multifunctional nucleic acid-binding protein with an extensive prion-like region that serves to regulate rather than drive condensate formation. Graphical Abstract

Different low-complexity regions of SFPQ play distinct roles in the formation of biomolecular condensates