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dc.contributor.authorFan, Z
dc.contributor.authorDevlin, JR
dc.contributor.authorHogg, SJ
dc.contributor.authorDoyle, MA
dc.contributor.authorHarrison, PF
dc.contributor.authorTodorovski, I
dc.contributor.authorCluse, LA
dc.contributor.authorKnight, DA
dc.contributor.authorSandow, JJ
dc.contributor.authorGregory, G
dc.contributor.authorFox, A
dc.contributor.authorBeilharz, TH
dc.contributor.authorKwiatkowski, N
dc.contributor.authorScott, NE
dc.contributor.authorVidakovic, AT
dc.contributor.authorKelly, GP
dc.contributor.authorSvejstrup, JQ
dc.contributor.authorGeyer, M
dc.contributor.authorGray, NS
dc.contributor.authorVervoort, SJ
dc.contributor.authorJohnstone, RW
dc.date.accessioned2020-11-17T03:42:01Z
dc.date.available2020-11-17T03:42:01Z
dc.date.issued2020-04-01
dc.identifierpii: aaz5041
dc.identifier.citationFan, Z., Devlin, J. R., Hogg, S. J., Doyle, M. A., Harrison, P. F., Todorovski, I., Cluse, L. A., Knight, D. A., Sandow, J. J., Gregory, G., Fox, A., Beilharz, T. H., Kwiatkowski, N., Scott, N. E., Vidakovic, A. T., Kelly, G. P., Svejstrup, J. Q., Geyer, M., Gray, N. S. ,... Johnstone, R. W. (2020). CDK13 cooperates with CDK12 to control global RNA polymerase II processivity. SCIENCE ADVANCES, 6 (18), https://doi.org/10.1126/sciadv.aaz5041.
dc.identifier.issn2375-2548
dc.identifier.urihttp://hdl.handle.net/11343/251582
dc.description.abstractThe RNA polymerase II (POLII)-driven transcription cycle is tightly regulated at distinct checkpoints by cyclin-dependent kinases (CDKs) and their cognate cyclins. The molecular events underpinning transcriptional elongation, processivity, and the CDK-cyclin pair(s) involved remain poorly understood. Using CRISPR-Cas9 homology-directed repair, we generated analog-sensitive kinase variants of CDK12 and CDK13 to probe their individual and shared biological and molecular roles. Single inhibition of CDK12 or CDK13 induced transcriptional responses associated with cellular growth signaling pathways and/or DNA damage, with minimal effects on cell viability. In contrast, dual kinase inhibition potently induced cell death, which was associated with extensive genome-wide transcriptional changes including widespread use of alternative 3' polyadenylation sites. At the molecular level, dual kinase inhibition resulted in the loss of POLII CTD phosphorylation and greatly reduced POLII elongation rates and processivity. These data define substantial redundancy between CDK12 and CDK13 and identify both as fundamental regulators of global POLII processivity and transcription elongation.
dc.languageEnglish
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0
dc.titleCDK13 cooperates with CDK12 to control global RNA polymerase II processivity
dc.typeJournal Article
dc.identifier.doi10.1126/sciadv.aaz5041
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentMicrobiology and Immunology
melbourne.source.titleScience Advances
melbourne.source.volume6
melbourne.source.issue18
melbourne.identifier.nhmrc454569
melbourne.identifier.nhmrc1077867
dc.rights.licenseCC BY-NC
melbourne.elementsid1449441
melbourne.openaccess.pmchttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190357
melbourne.contributor.authorJohnstone, Ricky
melbourne.contributor.authorSandow, Jarrod
melbourne.contributor.authorDoyle, Maria
melbourne.contributor.authorScott, Nichollas
melbourne.contributor.authorVervoort, Stephanus
melbourne.contributor.authorHogg, Simon
melbourne.contributor.authorDevlin, Jennifer
dc.identifier.eissn2375-2548
melbourne.identifier.fundernameidNHMRC, 454569
melbourne.identifier.fundernameidNHMRC, 1077867
melbourne.identifier.fundernameidVIC CANCER AGENCY, ECSG17018
melbourne.accessrightsOpen Access


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