SFPQ and NONO suppress RNA:DNA-hybrid-related telomere instability

Abstract

In vertebrates, the telomere repeat containing long, non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres. This results in the formation of R-loop structures, replication stress and telomere instability, but also contributes to alternative lengthening of telomeres (ALT). Here, we identify the TERRA binding proteins NONO and SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. NONO and SFPQ act as heterodimers to suppress fragility and homologous recombination at telomeres, respectively. Combining increased telomere fragility with unleashing telomere recombination upon NONO/SFPQ loss of function causes massive recombination events, involving 35% of telomeres in ALT cells. Our data identify the RNA binding proteins SFPQ and NONO as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids.

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

“…Some of the proteins bound to TERRA or RNA:DNA hybrids may act to reduce replication stress and suppress ALT. For example, TERRA -binding proteins SFPQ and NONO suppress telomeric RNA:DNA hybrids, and depletion of SFPQ increases APBs and telomere recombination in ALT + cells [80].…”

The Emerging Role of the RNA-Binding Protein SFPQ in Neuronal Function and Neurodegeneration

“…More recently, further involvement of SFPQ in the maintenance of genome stability has been demonstrated in relation to telomere maintenance, where the SFPQ/NONO heterodimer has been identified as a novel regulator at telomeres [ 46 ] ( Figure 2 E). It was shown that loss of SFPQ/NONO results in a significant increase in telomere recombination events and rapid alterations in telomere length in both telomerase-positive and negative cells.…”

rec-Y2H matrix screening reveals a vast potential for direct protein-protein interactions among RNA binding proteins

“…As positive controls, we used 5 pairs of RBPs that were detected in our screen and that had a least 5 independent literature sources in BioGRID confirming direct interaction (U2AF1-U2AF2; FMR1-FXR2; HNRNPK-QKI; RBFOX2-QKI; and SFPQ-NONO). In most cases, these pairs are also known to act as heterodimers and bind RNA as a complex (Fernandez et al, 2015;Li et al, 2018;Petti et al, 2019;Wu et al, 1999). As negative controls, we used randomly generated sets of RBP pairs of the same size as the screen hits.…”