Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(774)

Published: Nov. 20, 2024

Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription more than 70% inducible genes macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role Pol early elongation control inflammation, whether it can be modulated therapeutically, unknown. Genetic ablation a pause-stabilizing negative factor (NELF) did not affect baseline occupancy but enhanced transcriptional response paused anti-inflammatory to lipopolysaccharide followed by secondary attenuation inflammatory signaling vitro K/BxN serum transfer mouse model To pharmacologically disrupt cycle, we used two covalent inhibitors H-associated cyclin-dependent kinase 7 (CDK7), THZ1 YKL-5-124. Both reduced pausing murine human macrophages, broadly suppressed induction pro- genes, rapidly reversed preestablished macrophage polarization. In mice, CDK7 inhibition ameliorated both acute chronic progressive Lastly, down-regulated pathogenic gene expression signature synovial explants from patients with We propose that interfering targeting represents therapeutic opportunity arthritis other diseases.

Language: Английский

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Non-canonical CDK6 activity promotes cilia disassembly by suppressing axoneme polyglutamylation

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 224(2)

Published: Dec. 5, 2024

Tubulin polyglutamylation is a posttranslational modification that occurs primarily along the axoneme of cilia. Defective impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, precise mechanisms regulating proper remain vague. Here, we show cyclin-dependent kinase 6 (CDK6), but not its paralog CDK4, localizes to base suppresses by phosphorylating RAB11 family interacting protein 5 (FIP5) at site S641, critical regulator import glutamylases. S641 phosphorylation disrupts ciliary recruitment FIP5 association RAB11, thereby reducing Encouragingly, FDA-approved CDK4/6 inhibitor Abemaciclib can effectively restore in JBTS cells defective glutamylation. In summary, our study elucidates regulatory governing suggests developing CDK6-specific inhibitors could be promising therapeutic strategy enhance ciliopathy patients.

Language: Английский

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Coordinate control of the RNA polymerase II transcription cycle by CDK9-dependent, tripartite phosphorylation of SPT5

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 25, 2024

The RNA polymerase II (RNAPII) transcription cycle is regulated throughout its duration by reversible protein phosphorylation. elongation factor SPT5 contains two regions targeted cyclin-dependent kinase 9 (CDK9) and previously implicated in promoter-proximal pausing termination: the linker between KOWx-4 KOW5 domains carboxy-terminal repeat (CTR) 1, respectively. Here we show that phosphorylations KOWx-4/5 linker, CTR1 a third region, CTR2, coordinately control pause release, speed processing. Pausing was increased mutations preventing or CTR2 phosphorylation, but attenuated when both CTRs were mutated. Whereas mutating alone slowed repressed nascent transcription, simultaneous mutation of partially reversed effects. Nevertheless, led to aberrant splicing, dysregulated termination diminished steady-state mRNA levels, impaired cell proliferation more severely than did either single-CTR mutation. Therefore, tripartite phosphorylation times release regulates RNAPII rates positively negatively ensure productive viability.

Language: Английский

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Emerging roles of cyclin-dependent kinase 7 in health and diseases

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

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