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

TL;DR

The protein SFPQ helps prevent genome instability by managing R-loops at DNA repeats and recruiting H3.3 histones, with implications for cancer survival.

Contribution

SFPQ's role in recruiting DAXX to deposit H3.3 histones at R-loops in DNA repeats is newly identified as a mechanism to protect genome stability.

Findings

SFPQ suppresses R-loop mediated replication stress and DNA damage at repetitive DNA elements.

Loss of SFPQ leads to reduced H3.3 incorporation and activation of the cGAS/STING pathway.

SFPQ deficiency correlates with improved survival in sarcoma patients.

Abstract

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.

R-loops cause genome instability by creating conflicts with transcription and replication. Here the authors show that SFPQ binds R-loops at repetitive elements, recruits DAXX and maintains H3.3 deposition. Loss of SFPQ leads to genome instability and cGAS–STING activation, correlating with improved sarcoma patient survival.

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