On July 19, Associate Professor Lin Zhongyang from the Department of Biology of College of Science of Shantou University and the team of Professor HUEN, Michael Shing Yan from the College of Biomedical Sciences of the University of Hong Kong published a paper entitled "R-loop resolution by ARIP4 helicase promotes androgen-mediated transcription induction" in the journal Science Advances. Associate Professor Lin Zhongyang is one of the co-corresponding authors of the paper, and Shantou University is one of the collaborators. This study elucidates the function of R-loop helicase ARIP4 , illustrating its mechanism of action in transcriptional stress-promoting DNA fragmentation and inducing fusion genes. The discovery reveals a delicate balance between transcription and genome integrity, providing a new perspective on understanding the regulation of gene expression.
Transcription involves complex spatiotemporal dynamics, and the pause/release of RNA polymerase II in the proximal region of the promoter is a critical step in the regulation of gene expression, and proper regulation helps to coordinate transcription, DNA replication, and damage repair to maintain genome integrity. The proximal pause of the promoter of RNA polymerase II promotes the complementary pairing of nascent RNA strands with the DNA template to form a structure called the R loop. When the CTD region of RNA polymerase II was phosphorylated by Ser2, RNA polymerase II entered an elongated state, which was related to the decrease in the abundance of the R loop in the promoter region.
The study finds that the ARIP4 protein was able to bind to and unravel the R loop, thereby regulating the release of RNA polymerase II at the proximal (paused) end of the promoter. Using androgen receptor (AR) signaling as a model, the research team found that ARIP4 and paused RNA polymerase II co-occupied the transcription start site of the gene through chromatin immunoprecipitation sequencing analysis. At the same time, ARIP4 forms a complex with topoisomerase IIβ and mediates transient DNA double-strand breaks under hormone stimulation, releasing the DNA double-helix tension caused by transcription and accelerating the elongation of RNA polymerase II. In this process, the deletion of ARIP4 inhibits the release of RNA polymerase II at the proximal end of the promoter, resulting in the accumulation of R loops in the promoter region of highly transcribed AR target genes, which may increase the error rate of DNA damage repair and induce the production of fusion genes.
ARIP4 serves as a functional characterization of R-loop helicases and helps to elucidate complex gene expression regulation processes. This study provides a new perspective to explore the potential role of ARIP4 beyond AR signaling and its effects in other transcriptional environments, and also identifies potential targets for drug development based on novel gene regulatory strategies.
Lin Zhongyang, Associate Professor of the College of Science, and one of the member of Shrimp Immune Disease Team of Professor Zhang Yueling, has long been engaged in basic research on the epigenetic regulation of genes, including the epigenetic mechanism of bacteria-host interaction and the molecular basis of shrimp training immunity.
The link of R-loop Resolution by ARIP4 Helicase Promotes Androgen-mediated Transcription Induction”: https://www.science.org/doi/10.1126/sciadv.adm9577.
