Dual roles of DEAD-box RNA helicase Brr2 in genome stability regulation

Xiaolan Chen, Jin You, Qin Ma, Jiamei Lin, Yu Ji, Shi Li, Zhenxing Song, Rui Su, Ge Shan and Chuan Huang ()
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Xiaolan Chen: Chongqing University
Jin You: Chongqing University
Qin Ma: Chongqing University
Jiamei Lin: Chongqing University
Yu Ji: Chongqing University
Shi Li: Chongqing University
Zhenxing Song: Chongqing University
Rui Su: Chongqing University
Ge Shan: University of Science and Technology of China
Chuan Huang: Chongqing University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability.

Date: 2025
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DOI: 10.1038/s41467-025-64174-8

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