The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery

Liang Liu; Angela M Yu; Xiuye Wang; Lindsey V Soles; Xueyi Teng; Yiling Chen; Yoseop Yoon; Kristianna S K Sarkan; Marielle Cárdenas Valdez; Johannes Linder; Whitney England; Robert Spitale; Zhaoxia Yu; Ivan Marazzi; Feng Qiao; Wei Li; Georg Seelig; Yongsheng Shi

doi:10.1038/s41594-023-01161-x

The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery

Nat Struct Mol Biol. 2023 Dec;30(12):1947-1957. doi: 10.1038/s41594-023-01161-x. Epub 2023 Dec 12.

Authors

Liang Liu^#^{1

2}, Angela M Yu^#³, Xiuye Wang^{1

4}, Lindsey V Soles¹, Xueyi Teng⁵, Yiling Chen⁵, Yoseop Yoon¹, Kristianna S K Sarkan¹, Marielle Cárdenas Valdez¹, Johannes Linder⁶, Whitney England⁷, Robert Spitale^{7

8

9}, Zhaoxia Yu¹⁰, Ivan Marazzi⁵, Feng Qiao⁵, Wei Li⁵, Georg Seelig^{11

12}, Yongsheng Shi^{13

14}

Affiliations

¹ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA, USA.
² Center for Virus Research, University of California, Irvine, Irvine, CA, USA.
³ Department of Electrical and Computer Engineering, University of Washington, Seattle, Seattle, WA, USA.
⁴ Guangzhou Laboratory, Guangdong, China.
⁵ Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.
⁶ Department of Genetics, Stanford University, Stanford, CA, USA.
⁷ Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA.
⁸ Department of Chemistry, University of California, Irvine, Irvine, CA, USA.
⁹ Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
¹⁰ Department of Statistics, University of California, Irvine, Irvine, CA, USA.
¹¹ Department of Electrical and Computer Engineering, University of Washington, Seattle, Seattle, WA, USA. gseelig@uw.edu.
¹² Paul G Allen School of Computer Science and Engineering, University of Washington, Seattle, Seattle, WA, USA. gseelig@uw.edu.
¹³ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA, USA. yongshes@uci.edu.
¹⁴ Center for Virus Research, University of California, Irvine, Irvine, CA, USA. yongshes@uci.edu.

^# Contributed equally.

PMID: 38087090
DOI: 10.1038/s41594-023-01161-x

Abstract

JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3' processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3' processing machinery.

MeSH terms

Cell Line
RNA Precursors* / genetics
RNA Precursors* / metabolism
RNA Processing, Post-Transcriptional*
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

JTE 607
RNA Precursors
RNA, Messenger

Abstract

MeSH terms

Substances

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