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<p>R-loops are three-stranded nucleic acid structures composed of an RNA:DNA hybrid duplex and a displaced single-stranded DNA loop. Unscheduled or persistent R-loops drive genome instability by creating conflicts with transcription and replication. Up to 75% of the human genome comprises repetitive DNA elements that are prone to R-loop formation. We show that the RNA binding protein SFPQ suppresses R-loop mediated replication stress and DNA damage at repeat elements such as telomeres, (peri)-centromeres, LINE-1 and SINE elements. SFPQ exhibits in-vitro R-loop binding activity, associates with chromatin containing R-loops, and recruits the histone H3.3 specific chaperon DAXX to preserve a correct nucleosome template that counteracts R-loop accumulation. Loss of SFPQ results in DAXX displacement from repeat elements, reduced histone H3.3 incorporation, replication stress-mediated genome instability and the emergence of cytoplasmatic DNA. This leads to activation of innate immune signaling via the cGAS/STING pathway, ultimately correlating with improved survival of sarcoma patients.</p>

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SFPQ directs histone H3.3 deposition to R-loops in DNA repeats to protect genome stability

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Alessandro Ferrando,
  • Michele Giaquinto,
  • Luisa M. R. Napolitano,
  • Giulia Canarutto,
  • Alessandro Framarini,
  • Alice Gambelli,
  • Pamela Veneziano Broccia,
  • Annie Zappone,
  • Eleonora Petti,
  • Chiara Boncristiani,
  • Andrea Parlante,
  • Silvia Onesti,
  • Silvano Piazza,
  • Roberta Benetti,
  • Stefan Schoeftner

摘要

R-loops are three-stranded nucleic acid structures composed of an RNA:DNA hybrid duplex and a displaced single-stranded DNA loop. Unscheduled or persistent R-loops drive genome instability by creating conflicts with transcription and replication. Up to 75% of the human genome comprises repetitive DNA elements that are prone to R-loop formation. We show that the RNA binding protein SFPQ suppresses R-loop mediated replication stress and DNA damage at repeat elements such as telomeres, (peri)-centromeres, LINE-1 and SINE elements. SFPQ exhibits in-vitro R-loop binding activity, associates with chromatin containing R-loops, and recruits the histone H3.3 specific chaperon DAXX to preserve a correct nucleosome template that counteracts R-loop accumulation. Loss of SFPQ results in DAXX displacement from repeat elements, reduced histone H3.3 incorporation, replication stress-mediated genome instability and the emergence of cytoplasmatic DNA. This leads to activation of innate immune signaling via the cGAS/STING pathway, ultimately correlating with improved survival of sarcoma patients.