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SFPQ and NONO Suppress RNA:DNA-Hybrid-Related Telomere

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SFPQ and NONO Suppress RNA:DNA-Hybrid-Related Telomere ARTICLE https://doi.org/10.1038/s41467-019-08863-1 OPEN SFPQ and NONO suppress RNA:DNA-hybrid- related telomere instability Eleonora Petti1,2,6, Valentina Buemi1,2, Antonina Zappone1,2, Odessa Schillaci1, Pamela Veneziano Broccia1,2, Roberto Dinami1,2,6, Silvia Matteoni 3, Roberta Benetti4,5 & Stefan Schoeftner1,2 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 1234567890():,; 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 telo- meres, 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. 1 Genomic Stability Unit, Laboratorio Nazionale—Consorzio Interuniversitario per le Biotecnologie (LNCIB), Padriciano 99, 34149 Trieste, Italy. 2 Department of Life Sciences, Università degli Studi di Trieste, Via E. Weiss 2, 34127 Trieste, Italy. 3 Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS—Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy. 4 Dipartimento di Area Medica (Dame), Università degli Studi di Udine, p.le Kolbe 1, 33100 Udine, Italy. 5 Cancer Epigenetics Unit, Laboratorio Nazionale—Consorzio Interuniversitario per le Biotecnologie (LNCIB), Padriciano 99, 34149 Trieste, Italy. 6Present address: Oncogenomic and Epigenetic Unit, IRCCS—Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy. These authors contributed equally: Eleonora Petti, Valentina Buemi, Antonina Zappone. Correspondence and requests for materials should be addressed to S.S. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:1001 | https://doi.org/10.1038/s41467-019-08863-1 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-08863-1 elomeres are heterochromatic structures that protect but also TERRA, a telomere repeat [UUAGGGn] containing long Teukaryotic chromosome ends from an unwanted elicitation non-coding RNA5,6. In human cancer cells, DNA methylation of a DNA damage response, telomere degradation and sensitive promoters located in subtelomeres recruit RNA Poly- aberrant recombination1–3. Incomplete replication of chromo- merase II that uses the CCCTAA-repeat containing telomere some ends results in progressive shortening of telomeres, finally strand as template for the transcription of TERRA5–11. TERRA is leading to telomere dysfunction and irreversible cell cycle arrest, heterogeneous in size and a subfraction of TERRA has been also referred to as replicative senescence4. Core components of shown to localize to telomeric chromatin5,6,11. Accordingly, vertebrate telomeric chromatin comprise the multi-protein TERRA is reported to act as scaffold that promotes the con- complex “shelterin” that has a key role in telomere protection centration of proteins or enzymatic activities at telomeres, thereby a 6 b c 6 6 MW NE Biotin- r[EGFP] Biotin- r[UUAGGG] Beads 150 kDa 100 kDa hnRNP U * SFPQ NE Beads Biotin-r[EGFP] Biotin-r[UUAGGG] Beads NE Biotin-r[UUAGGG] * Bbiotin-r[EGFP] 75 kDa Not * indentified 100 kDa SFPQ 100 kDa SFPQ FUS NONO NONO * NONO 50 kDa 50 kDa 50 kDa * hnRNP U FUS FUS * hnRNP H1 50 kDa 50 kDa * hnRNP H2 Actin Actin * hnRNP F 37 kDa 37 kDa * hnRNP D0 * mESCs H1299 37 kDa * DAZAP1 * hnRNP A/B * hnRNP A3 mESCs hnRNP A3 hnRNP A2/B1 d NONO TRF2 TRF2/NONO f 50.7 ± 6.4 80 n = 100 N = 3 60 19.0 ± 2.1 40 n = 100 N = 3 1 μm 20 U-2 OS events per nucleus Number of co-localization 0 e SFPQ TRF1 TRF1/SFPQ NONO/TRF2 SFPQ/TRF1 1 μm U-2 OS g h p = 0.002 p = 0.005 1:10 1:100 IgG M TRF2 NONO FUS H3 Tot 1:1000 IgG R SFPQ 15 p = 0.04 Telomere probe s.e. 7.6 ± 1.2 N = 3 10 5.7 ± 0.7 Telomere probe l.e. 3.3 ± 0.8 N = 3 N = 3 5 1.0 telomeric repeats AluY probe Immunoprecipitated N = 3 (control IgG R set «1») 0 FUS IgG R NONO SFPQ 2 NATURE COMMUNICATIONS | (2019) 10:1001 | https://doi.org/10.1038/s41467-019-08863-1 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-08863-1 ARTICLE Fig. 1 SFPQ and NONO interact with TERRA and localize to telomere repeats. a Silver staining of SDS-PAGE gels of eluates obtained from RNA-pull-down experiments using biotinylated r[UUAGGG]6, biotinylated r[EGFP] RNA oligonucleotides or empty beads. Candidate TERRA interacting proteins identified by mass spectrometry are indicated. NE, nuclear extract used as input; MW, molecular weight marker. b, c Western blotting analysis of RNA-pull-down eluates using specific anti-NONO and anti-SFPQ antibodies confirms binding specificity of NONO and SFPQ for UUAGGG RNA repeats in mESCs (b) and H1299 cells (c). FUS was previously reported to interact with TERRA42. Actin was used as loading control; NE, nuclear extract was used as input. Source blots are available as Supplementary Figure 6 and 7. d Representative image of co-localization events (arrowheads) between NONO and the shelterin protein TRF2 as determined by confocal microscopy in U-2 OS cells. e Representative image of co-localization events (arrowheads) between SFPQ and the shelterin protein TRF1 by confocal microscopy in U-2 OS cells. f Quantification of d and e. Mean number of NONO-TRF2 and SFPQ-TRF1 co-localization events per nucleus is shown. Error bars indicate standard deviation. n = number of analyzed nuclei. g Chromatin immunoprecipitation experiments (ChIP) using U-2 OS cells and mouse anti-TRF2, rabbit anti-histone H3, rabbit anti-FUS, rabbit anti-NONO, and rabbit anti-SFPQ antibodies. Mouse and rabbit control IgGs (IgG M/IgG R) were used as negative control. Serial dilutions of chromatin extract (input) prepared from U-2 OS cells were loaded. h Quantification of three independent ChIP experiments, average enrichment of telomeric repeats is indicated; s.e.: short exposure; l.e.: long exposure. f, h N, number of independent experiments, whiskers indicate standard deviation; a two-tailed Student’s t-test was used to calculate p-values. Source data is provided as a Supplementary Information File. Scale bar, 1 μm. siRNAs listed in Supplementary Table 1 impacting on chromatin structure, chromosome end protection, telomere fragility; in contrast SFPQ represents a powerful barrier replication but also telomere maintenance by telomerase12–14. to homologous recombination at telomeres. Accordingly, com- Importantly, due to its G-rich sequence content, TERRA is prone bined loss of NONO and SFPQ results in a massive increase of to form RNA:DNA hybrids with the C-rich telomeric strand. This telomere recombination events and rapid alterations in telomere results in the displacement of the TTAGGG repeat containing length in both, telomerase-positive and negative cells. Our study telomere strand, giving rise to so-called “R-loop” structures15–19. introduces NONO and SFPQ as novel regulators of RNA:DNA- In a natural context, R-loops are relevant for the regulation of hybrid management that may open new inroads in defining gene expression, chromatin structure and IgG class switch strategies that aim to target recombination-based pathways of recombination20–29. However, R-loops can represent obstacles to telomere maintenance in human cancer. DNA replication resulting in replicative stress, chromosome fra- gility, DNA lesions and the activation of recombination-mediated DNA repair that can finally lead to chromosome Results rearrangements28,30–34. Recent studies showed that several bio- NONO and SFPQ are TERRA interacting proteins.Inorderto logical pathways prevent or resolve RNA:DNA-hybrid structures identify novel TERRA interacting proteins, we performed at eukaryotic telomeres. In yeast, loss of the 5′ to 3′ exonuclease, TERRA RNA-pull-down experiments using mouse embryonic Rat1p was linked with increased abundance of telomeric RNA: stem cells that maintain telomeres via telomerase dependent DNA hybrids35. Loss of the THO complex in yeast results in and independent telomere maintenance pathways39. Biotiny- TERRA accumulation at telomeres, R-loop formation and lated RNA oligonucleotides containing six UUAGGG repeats or increased telomere recombination rates16. Further, lack of the flap control oligonucleotides were incubated with nuclear extracts endonuclease 1 (FEN1), a canonical lagging strand DNA repli- obtained from mouse embryonic stem cells and recovered by cation protein, leads to replicative stress at telomeres, caused by using stretpavidine coated agarose beads. Eluates from TERRA increased telomeric RNA:DNA hybrids36. In yeast and human and control RNA-pull-down experiments were processed by gel cells, a particular relevance has been attributed to RNaseH that electrophoresis. Silver staining revealed a series of proteins that antagonize R-loop formation by degrading RNA paired with were specifically eluted from TERRA RNA oligonucleotides DNA15,17,35. In yeast,
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