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PreprintCited by 21Genomics and Chromatin DynamicsRNA Research and SplicingChromatin Remodeling and Cancer

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PAF1C allosterically activates CDK12/13 kinase during RNAPII transcript elongation

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Lopez Martinez, David, Todorovski, Izabela, Noe Gonzalez, Melvin, Rusimbi, Charlotte, Blears, Daniel, Khallou, Nessrine, Han, Zhong, Dirac-Svejstrup, A. Barbara, Svejstrup, Jesper Q.·2024·Molecular Cell
DOI 10.1101/2024.10.14.618141

Preprint — published as 10.1016/j.molcel.2025.04.012

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Abstract

The mechanisms ensuring temporally correct, site-specific phosphorylation of the RNA polymerase II C-terminal domain (CTD) by cyclin-dependent kinases (CDKs) during the transcription cycle remain poorly understood. Here, we present results from in vitro reconstitution of CTD phosphorylation combined with in vivo evidence to show that human CDK12 and CDK9 both co-phosphorylate CTD Serine 5 and Serine 2. However, only phosphorylation by CDK12 is stimulated by association with the elongation-specific factor PAF1C, in which the CDC73 subunit contains a short, conserved motif capable of association with and activation of CDK12/Cyclin K. This motif is necessary for cell proliferation and crucial for CTD phosphorylation and transcript elongation. Together, these data provide new insight into basic mechanisms ensuring CDK specificity in the RNAPII transcription cycle. One-Sentence Summary: PAF1C facilitates RNAPII phosphorylation in gene bodies through direct contacts with the active site of CDK12/13.

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Metadata

Authors
Lopez Martinez, D., Todorovski, I., Noe Gonzalez, M., Rusimbi, C., Blears, D., Khallou, N., Han, Z., Dirac-Svejstrup, A. B., & Svejstrup, J. Q.
Affiliations
University of Copenhagen (DK)
Corresponding author
Svejstrup, Jesper Q.
ORCID
Venue
Molecular Cell
Publisher
openRxiv
Published
2024-10-16
Volume
85
Issue
10
Pages
1952-1967.e8
ISSN
1097-2765 (ISSN-L)
DOI
10.1101/2024.10.14.618141
OpenAlex
W4409995455
Cited by
21
References
1
Citations by year
2026: 16 · 2025: 5
FWCI
6.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
Funders
  • European Molecular Biology Organization (ALTF 847-2023, ALTF 2020-260)
  • Francis Crick Institute (NNF19OC0055875, DNRF153)
  • European Commission (HORIZON2020, 101023584)
  • National Research Foundation
  • Danmarks Grundforskningsfond (NNF19OC0055875, DNRF166, DNRF153)
  • Novo Nordisk
  • Novo Nordisk Fonden (DNRF153, NNF19OC0055875)
  • H2020 Marie Skłodowska-Curie Actions
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
Paf1 complex, CDK12, CDK13, cyclin K, CDC73, C-terminal domain phosphorylation, RNA polymerase II, transcription elongation, cell proliferation, transcription cycle
MeSH terms
Protein Domains, Chromatin, Enzyme Activation, HeLa Cells, Humans, Nuclear Proteins, Phosphorylation, RNA Polymerase II, Serine, Transcription Factors, CDC2 Protein Kinase, Cyclin-Dependent Kinases, Transcriptional Elongation Factors, Cell Proliferation, HEK293 Cells, Transcription Elongation, Genetic

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