Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12540/80
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dc.contributor.authorZhang, Boen_US
dc.contributor.authorZhong, Xuelinen_US
dc.contributor.authorSauane, Moiraen_US
dc.contributor.authorZhao, Yihongen_US
dc.contributor.authorZheng, Zhi-Liangen_US
dc.date.accessioned2020-07-09T02:23:02Z-
dc.date.available2020-07-09T02:23:02Z-
dc.date.issued2020-
dc.identifier.citationZhang, B., Zhong, X., Sauane, M., Zhao, Y., & Zheng, Z. L. (2020). Modulation of the Pol II CTD phosphorylation code by Rac1 and Cdc42 small GTPases in cultured human cancer cells and its implication for developing a synthetic-lethal cancer therapy. Cells, 9(3), 621.en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12540/80-
dc.description.abstractRho GTPases, including Rho, Cdc42, Rac and ROP subfamilies, are key signaling molecules in RNA polymerase II (Pol II) transcriptional control. Our prior work has shown that plant ROP and yeast Cdc42 GTPases similarly modulate Ser2 and Ser5 phosphorylation status of the C-terminal domain (CTD) of the Pol II largest subunit by regulating CTD phosphatase degradation. Here, we present genetic and pharmacological evidence showing that Cdc42 and Rac1 GTPase signaling modulates a similar CTD Ser2 and Ser5 phosphorylation code in cultured human cancer cells. While siRNA knockdown of Cdc42 and Rac1, respectively, in HeLa cells increased the level of CTD Ser phosphatases RPAP2 and FCP1, they both decreased the level of CTD kinases CDK7 and CDK13. In addition, the protein degradation inhibitor MG132 reversed the effect of THZ1, a CDK7 inhibitor which could decrease the cell number and amount of CDK7 and CDK13, accompanied by a reduction in the level of CTD Ser2 and Ser5 phosphorylation and DOCK4 and DOCK9 (the activators for Rac1 and Cdc42, respectively). Conversely, treatments of Torin1 or serum deprivation, both of which promote protein degradation, could enhance the effect of THZ1, indicating the involvement of protein degradation in controlling CDK7 and CDK13. Our results support an evolutionarily conserved signaling shortcut model linking Rho GTPases to Pol II transcription across three kingdoms, Fungi, Plantae and Animalia, and could lead to the development of a potential synthetic-lethal strategy in controlling cancer cell proliferation or death.en_US
dc.format.extent17 pagesen_US
dc.format.mimetypeapplication/pdfen_US
dc.language.isoengen_US
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)en_US
dc.relation.ispartofCellsen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/-
dc.titleModulation of the Pol II CTD phosphorylation code by Rac1 and Cdc42 small GTPases in cultured human cancer cells and its implication for developing a synthetic-lethal cancer therapyen_US
dc.typeArticleen_US
dc.rights.licenseAttribution-NonCommercial 4.0 International (CC BY-NC 4.0)en_US
dc.identifier.doi10.3390/cells9030621-
dc.subject.keywordsRhoen_US
dc.subject.keywordsRac1en_US
dc.subject.keywordsCdc42en_US
dc.subject.keywordsPol IIen_US
dc.subject.keywordsCTD codeen_US
dc.subject.keywordsCDK7en_US
dc.subject.keywordsDOCK4en_US
dc.subject.keywordsDOCK9en_US
dc.subject.keywordsTHZ1en_US
dc.subject.keywordsTorin1en_US
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