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

作者：Xiaolan Chen, Jin You, Qin Ma, Jiamei Lin, Yu Ji, Li Shi, Zhenxing Song, Rui Su, Ge Shan, Chuan Huang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64174-8 · 被引用次数：8 · 研究领域：RNA Research and Splicing、Circular RNAs in diseases、RNA modifications and cancer

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. R-loops are DNA-RNA hybrids that can cause genome instability if not properly controlled. Here, the authors show that the RNA helicase Brr2 prevents harmful circRNA-associated R-loops, thereby safeguarding transcription and cell division.