Dynamic U2AF cycling defines two phases of cotranscriptional pre-mRNA splicing

Distinguishing functional splice sites from abundant cryptic sites in precursor messenger RNAs (pre-mRNAs) represents a fundamental challenge in decoding mammalian genomes. We demonstrate that the specific RNA polymerase II (Pol II) subunit RPB9 directly interacts with the 3' AG dinucleotide binding factor U2AF1 to initiate 3' splice site recognition. Combined with recent structural insights into Pol II-mediated 5' splice site selection, these findings support a cotranscriptional mechanism to recognize paired 3' and 5' splice sites across individual exons. These initial exon definition events facilitate the recruitment of U2AF2 to heterodimerize with U2AF1, which also triggers U2AF1 release from elongating Pol II. Collectively, these results reveal dynamic U2AF cycling that partitions Pol II subunit-facilitated splice site recognition and subsequent Pol II-independent spliceosome assembly steps during cotranscriptional splicing.

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Publication Details

Journal
Science
Published
2025-09-25
DOI
https://doi.org/10.1126/science.adj9141
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
1.61
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article

Dynamic U2AF cycling defines two phases of cotranscriptional pre-mRNA splicing

Tan Wu, Ji Xiong, Yanhui Xu, Li Jiang et al.
2 citations
Science
RNA Research and Splicing
1.61
article

Dynamic U2AF cycling defines two phases of cotranscriptional pre-mRNA splicing

Tan Wu, Ji Xiong, Yanhui Xu, Li Jiang, Ruixue Wan, Yuanjun Li, Lan‐Tao Gou, Xiangjuan Du, Changwei Shao, Yaping Ge, Yajing Hao, Rui Wang, Dong Wang, Hui Wang, Rui Bai, Xiang‐Dong Fu, Xizi Chen
article en
2 citations

Abstract

Distinguishing functional splice sites from abundant cryptic sites in precursor messenger RNAs (pre-mRNAs) represents a fundamental challenge in decoding mammalian genomes. We demonstrate that the specific RNA polymerase II (Pol II) subunit RPB9 directly interacts with the 3' AG dinucleotide binding factor U2AF1 to initiate 3' splice site recognition. Combined with recent structural insights into Pol II-mediated 5' splice site selection, these findings support a cotranscriptional mechanism to recognize paired 3' and 5' splice sites across individual exons. These initial exon definition events facilitate the recruitment of U2AF2 to heterodimerize with U2AF1, which also triggers U2AF1 release from elongating Pol II. Collectively, these results reveal dynamic U2AF cycling that partitions Pol II subunit-facilitated splice site recognition and subsequent Pol II-independent spliceosome assembly steps during cotranscriptional splicing.

ScienceVol. 389(6767)
Shanghai Medical College of Fudan University (CN), Beijing Institute of Genomics (CN), Westlake University (CN), University of California San Diego (US), Fudan University Shanghai Cancer Center (CN), Center for Excellence in Molecular Cell Science (CN), Center for Life Sciences (CN)
Openalex Percentile: Top 15%
RNA Research and Splicing
1.61
DOISourceOpenAlex
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