The degradation mechanism of circular intronic RNAs is a mystery in the research on circular RNAs. Circular intronic RNAs (ciRNAs) are a class of covalently closed RNA molecules that stably exist in the cell due to the intron lariat not debranching normally during the precursor mRNA splicing.
The Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences andChen Lingling's research group have discoveredthe molecular mechanism in which some circular intronic RNAs are recognized and degraded by RNase H1 in the form of DNA-RNA hybrid (R-loop). They also suggest that this process may be involved in the transcriptional regulation of parental genes. The article "Linking circular intronic RNA degradation and function in transcription by RNase H1" was published as a cover article in SCIENCE CHINA Life Sciences on August 25.
Previous work by the research group revealed that cis-regulatory elements near the 5' splicing site and branching site are involved in the generation and stable presence of ciRNAs, and found that ciRNAs accumulate near the transcription site and promote the transcription of parental genes through unknown mechanisms (Zhang et al., MolCell, 2013). In this recent study, RNase H1 is identified as regulating the degradation of a portion of ciRNAs by screening for known endonucleases. RNase H1 is known to be an endonuclease that specifically degrades the RNA strands in the R-loop structure. It is found that some ciRNAs have a high GC content and tend to form R-loop at their transcription sites in cells, which are then recognized and degraded by RNase H1. Intracellularly, ciRNAs are localized within the nucleus and partially colocalized with RNase H1. Examination of the RNA polymerase II (Pol II) transcription extension rate (TER) of newborn transcripts shows that the TER of Pol II producing ciRNA's genes is higher than that of Pol II which does not produce ciRNA's genes. In addition, in vitro experiments reveal that ci-ankrd52 has a unique secondary structure that allows it to form a more stable R-loop with the DNA of the parent gene by comparison with linear RNA with the same sequence. Further in vitro competition experiments reveal that ci-ankrd52, one of the ring RNAs degraded by RNase H1, competes with the precursor RNA to bind the parental gene DNA, suggesting that it may be involved in the release of R-loop precursor RNA, which is conducive to the transcriptional extension of RNA polymerase II (Pol II). It is worth noting that the importance of this mechanism in cells needs to be further explored due to the current lack of specific means to monitor and distinguish ciRNA or precursor RNA-forming R-loops in real time within cells, as well as tools for efficient and specific knockout of ciRNA.
Schematic diagram that the partially "open" single-stranded RNA secondary structure of ci-ankrd52 facilitates the formation of the in vitro SHAPE-MaP method of R-loop A with template DNA; Schematic diagram of the in vitro conformation of B circular or linear ankrd52 in the presence or absence of template DNA; C and D remove or replace the "open" single-stranded RNA secondary structure of ci-ankrd52 (212-248 nt) to inhibit the formation of R-loop with template DNA
Dr.Li Xiang from HIAS is the first author of the paper, and research fellowChen Lingling is the corresponding author. The members of Chen Lingling's research group, including postdoctoral researcherZhang Jialin, doctoral candidatesLiu Xiaoqi andGao Xiang, staffZhang Jun and graduated doctoral studentZhang Yang, participated in part of the project. The research is also assisted by Yang Li, a research fellow of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (formerly Institute of Computational Biology), and his doctoral candidates Lei Yunni, Xue Wei, and Nan Fang, as well as Professor Sun Qianwen of Tsinghua University in the R-loop analysis process. This project was supported by the National Natural Science Foundation of China (91940303, 31725009, 31730111, 31925011), HHMI International Program (55008728), and the Young Talent Support Project of China Association for Science and Technology (2020QNRC001).
The article was quickly reviewed and published online on SCIENCE CHINA Life Sciences through the green channel within 7 working days.
Li, X., Zhang, J.L., Lei, Y.N., Liu, X.Q.,Xue, W., Zhang, Y., Nan, F., Gao, X., Zhang, J., Wei, J., et al.(2021).Linking circular intronic RNA degradation and function in transcription by RNase H1. Sci China Life Sci64,https://doi.org/10.1007/s11427-021-1993-6
Zhang, Y., Zhang, X.O., Chen, T., Xiang, J.F.,Yin, Q.F., Xing, Y.H., Zhu, S.S., Yang, L. and Chen L.L. (2013). Circularintronic long noncoding RNAs. Mol Cell 51,https://doi.org/10.1016/j.molcel.2013.08.017
Source | School of Life Science
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