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The golden anniversary of eukaryotic transcription
The three eukaryotic DNA-dependent RNA polymerases (Pol) — the nucleoplasmic Pol II and Pol III and the nucleolar Pol I — were isolated 50 years ago. To celebrate this anniversary, Nature Reviews Molecular Cell Biology and Nature Structural & Molecular Biology present a collection of Reviews and Perspectives that showcase our current understanding of transcription regulation in eukaryotes.
Transcription-blocking DNA lesions (TBLs) cause transcription stress and are repaired by transcription-coupled nucleotide excision repair (TC-NER). TBL detection by the stalling of RNA polymerase II is highly efficient but may interfere with repair, and overall with transcription and replication. Consequently, TC-NER deregulation causes hereditary disorders with complex genotype–phenotype correlations.
In this Review, Bob Roeder offers a personal, historical perspective of the landmark studies that elucidated the mechanism and regulation of eukaryotic transcription over five decades, from the initial discovery of three nuclear RNA polymerases to the structural, genomic and imaging approaches that continue to expand our understanding of the function of complex regulatory networks.
Core promoters of RNA polymerase II enable highly regulated transcription initiation by integrating cues from distal enhancers. The emerging diversity of core promoters defines distinct transcription programmes and can explain the nature and outcome of transcription initiation at gene start sites and at enhancers.
Genome organization can regulate gene expression, but can gene expression regulate genome organization? Recent studies reveal that, although not required for higher-level genome organization, transcription has a role in the formation and stabilization of genomic subdomains and enhancer–promoter interactions.
Recent data indicate that various transcription factors and RNA polymerase II bind to mitotic chromatin and that thousands of genes remain transcriptionally active in mitosis, contradicting the view that mitotic cells are transcriptionally silenced. These mechanisms provide mitotic transcriptional memory, which allows re-establishment of cell-type-specific gene expression following division.
Transcription elongation by RNA polymerase II (Pol II) involves pausing of Pol II at promoter-proximal regions. Pol II release into gene bodies (productive elongation) is controlled by many transcription-specific factors, enhancers and factors that are canonically associated with genome maintenance.
The evolutionarily conserved mediator of RNA polymerase II transcription (Mediator) complex is a general regulator of transcription. Recent structural and functional studies have provided important insights into the mechanisms of transcription activation by Mediator and have also revealed a new function of this complex in genome organization and suggested that it could be therapeutically targeted in disease.
The carboxy-terminal domain (CTD) of RNA polymerase II is a repetitive and unstructured domain that is dynamically modified by post-translational modifications, which collectively constitute the 'CTD code'. Recent studies have revealed how CTD function is also promoted by phase separation in the presence of other low-complexity domains.
James Kadonaga provides a retrospective of the biochemical analyses that demonstrated the role of chromatin in the regulation of RNA polymerase II transcription.
This personal Perspective by Joan and Ron Conaway describes the biochemical identification and characterization of three key transcription elongation factors, TFIIS, Elongin and ELL, and summarizes how the delineation of their functions has informed the understanding of the regulatory mechanisms that control elongation by RNA polymerase II.
This historical Perspective by John Lis summarizes the array of complementary biochemical, genetic, optical and genome-wide approaches that have enabled dissection of eukaryotic transcriptional mechanisms in their native, cellular environment, and considers the future insights offered by emerging technologies of ever-increasing sensitivity and resolution.