Targeting Spt5-Pol II by Small-Molecule Inhibitors Uncouples Distinct Activities and Reveals Additional Regulatory Roles.

Targeting Spt5-Pol II by Small-Molecule Inhibitors Uncouples Distinct Activities and Reveals Additional Regulatory Roles.

Publication date: Sep 25, 2019

Spt5 is a conserved and essential transcription elongation factor that promotes promoter-proximal pausing, promoter escape, elongation, and mRNA processing. Spt5 plays specific roles in the transcription of inflammation and stress-induced genes and tri-nucleotide expanded-repeat genes involved in inherited neurological pathologies. Here, we report the identification of Spt5-Pol II small-molecule inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on promoter-proximal pausing, NF-_705B activation, and expanded-repeat huntingtin gene transcription. Using SPIs, we identified Spt5 target genes that responded with profoundly diverse kinetics. SPIs uncovered the regulatory role of Spt5 in metabolism via GDF15, a food intake- and body weight-inhibitory hormone. SPIs further unveiled a role for Spt5 in promoting the 3′ end processing of histone genes. While several SPIs affect all Spt5 functions, a few inhibit a single one, implying uncoupling and selective targeting of Spt5 activities. SPIs expand the understanding of Spt5-Pol II functions and are potential drugs against metabolic and neurodegenerative diseases.

Bahat, A., Lahav, O., Plotnikov, A., Leshkowitz, D., and Dikstein, R. Targeting Spt5-Pol II by Small-Molecule Inhibitors Uncouples Distinct Activities and Reveals Additional Regulatory Roles. 06700. 2019 Mol Cell.

Concepts Keywords
Elongation Factor Promoter
Histone FACT
Hormone Histone
Huntingtin Huntingtin
Inflammation Transcription
Kinetics DSIF
Metabolism Gene expression
MRNA Branches of biology
Neurodegenerative Diseases Specific transcription inflammation
Neurological
Nucleotide
Pathologies
Proximal
Small Molecule
Stress
Transcription

Semantics

Type Source Name
disease DOID Huntington disease
disease MESH Huntington disease
pathway BSID Neurodegenerative Diseases
disease MESH neurodegenerative diseases
gene UNIPROT GDF15
pathway BSID Metabolism
gene UNIPROT HTT
pathway BSID mRNA Processing
disease MESH inflammation
gene UNIPROT SUPT5H

Original Article

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