| Structural highlights
Function
[CPSF3_HUMAN] Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Has endonuclease activity, and functions as mRNA 3'-end-processing endonuclease. Also involved in the histone 3'-end pre-mRNA processing. U7 snRNP-dependent protein that induces both the 3'-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5' to 3' exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5'-ACCCA-3' sequence in the histone pre-mRNA leaving a 3'hydroxyl group on the upstream fragment containing the stem loop (SL) and 5' phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5' to 3' exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner.[1] [2] [3] [4]
Publication Abstract from PubMed
The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.
CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.,Ross NT, Lohmann F, Carbonneau S, Fazal A, Weihofen WA, Gleim S, Salcius M, Sigoillot F, Henault M, Carl SH, Rodriguez-Molina JB, Miller HR, Brittain SM, Murphy J, Zambrowski M, Boynton G, Wang Y, Chen A, Molind GJ, Wilbertz JH, Artus-Revel CG, Jia M, Akinjiyan FA, Turner J, Knehr J, Carbone W, Schuierer S, Reece-Hoyes JS, Xie K, Saran C, Williams ET, Roma G, Spencer M, Jenkins J, George EL, Thomas JR, Michaud G, Schirle M, Tallarico J, Passmore LA, Chao JA, Beckwith REJ Nat Chem Biol. 2020 Jan;16(1):50-59. doi: 10.1038/s41589-019-0424-1. Epub 2019, Dec 9. PMID:31819276[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 2004 Feb 11;23(3):616-26. Epub 2004 Jan 29. PMID:14749727 doi:http://dx.doi.org/10.1038/sj.emboj.7600070
- ↑ Ryan K, Calvo O, Manley JL. Evidence that polyadenylation factor CPSF-73 is the mRNA 3' processing endonuclease. RNA. 2004 Apr;10(4):565-73. PMID:15037765
- ↑ Kolev NG, Yario TA, Benson E, Steitz JA. Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3'-end maturation. EMBO Rep. 2008 Oct;9(10):1013-8. doi: 10.1038/embor.2008.146. Epub 2008 Aug 8. PMID:18688255 doi:http://dx.doi.org/10.1038/embor.2008.146
- ↑ Mandel CR, Kaneko S, Zhang H, Gebauer D, Vethantham V, Manley JL, Tong L. Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease. Nature. 2006 Dec 14;444(7121):953-6. Epub 2006 Nov 26. PMID:17128255 doi:10.1038/nature05363
- ↑ Ross NT, Lohmann F, Carbonneau S, Fazal A, Weihofen WA, Gleim S, Salcius M, Sigoillot F, Henault M, Carl SH, Rodriguez-Molina JB, Miller HR, Brittain SM, Murphy J, Zambrowski M, Boynton G, Wang Y, Chen A, Molind GJ, Wilbertz JH, Artus-Revel CG, Jia M, Akinjiyan FA, Turner J, Knehr J, Carbone W, Schuierer S, Reece-Hoyes JS, Xie K, Saran C, Williams ET, Roma G, Spencer M, Jenkins J, George EL, Thomas JR, Michaud G, Schirle M, Tallarico J, Passmore LA, Chao JA, Beckwith REJ. CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma. Nat Chem Biol. 2020 Jan;16(1):50-59. doi: 10.1038/s41589-019-0424-1. Epub 2019, Dec 9. PMID:31819276 doi:http://dx.doi.org/10.1038/s41589-019-0424-1
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