Illustration of Phosphorylation Cascade

Decoding the Blueprint: How Protein Phosphorylation Ensures Genetic Accuracy

Reese Marlowe in Science & Nature September 2025 • 4 min read.

"Unlocking the secrets of Spt6 phosphorylation and its pivotal role in maintaining transcriptional fidelity."

Our genetic code, DNA, relies on a complex series of mechanisms to be interpreted accurately. One key process is transcription, where RNA polymerase II (RNAPII) reads DNA to create RNA molecules that serve as templates for protein synthesis. Spt6, a histone chaperone, is crucial in this process, associating with RNAPII and depositing nucleosomes—the structural units of DNA packaging—in the wake of transcription.

While Spt6's role in nucleosome deposition is well-established, whether this function is influenced by post-translational modifications—chemical alterations that affect protein activity—has remained unclear. Recent research has shed light on this question, uncovering a critical role for casein kinase II (CKII) phosphorylation of Spt6.

This article delves into the groundbreaking findings of Dronamraju et al. (2018), revealing how CKII phosphorylation of Spt6 is essential for maintaining nucleosome occupancy at the 5' ends of genes. This process prevents aberrant antisense transcription, ensures transcriptional directionality, and ultimately enforces transcriptional fidelity.

The Key Role of CKII Phosphorylation in Spt6 Function

The study by Dronamraju et al. (2018) pinpoints that casein kinase II (CKII) phosphorylation of Spt6 is essential for nucleosome occupancy at the 5' ends of genes, preventing aberrant antisense transcription and enforcing transcriptional directionality. CKII modifies the unstructured N terminus of Spt6, a region known to interact with histones H3/H4 and Spn1, an important protein for chromatin remodeling.

The scientists found that mutations preventing CKII phosphorylation led to reduced global nucleosome occupancy and increased aberrant antisense transcription from gene 5' ends. Conversely, mimicking constitutive Spt6 phosphorylation largely rescued these defects. These findings underscore the importance of phosphorylation in maintaining genetic stability.

Prevents Aberrant Transcription: CKII phosphorylation of Spt6 prevents both sense and antisense transcription errors, ensuring that genes are read in the correct direction and from the appropriate starting point.
Maintains Genomic Stability: By preventing inappropriate transcription, CKII phosphorylation of Spt6 helps to maintain the integrity of the genome, avoiding the production of non-functional or harmful RNA molecules.
Promotes Spt6-Spn1 Interaction: CKII phosphorylation facilitates the interaction between Spt6 and Spn1, a crucial step in chromatin reassembly and Spt6 recruitment to genes.

The study suggests that CKII phosphorylation of Spt6 facilitates interaction with Spn1, which promotes nucleosome occupancy at gene 5' ends to enforce transcription accuracy and directionality. During transcription elongation, CKII phosphorylation of Spt6 ensures that Spn1 binds fully, promoting nucleosome occupancy at gene 5' ends and maintaining transcription accuracy.

The Implications for Future Research

In summary, this article illuminates the crucial role of CKII-mediated Spt6 phosphorylation in maintaining transcriptional fidelity. It emphasizes the importance of understanding post-translational modifications in histone chaperone function and opens avenues for future research into the mechanisms that regulate gene expression and maintain genomic stability. Further studies may explore how CKII phosphorylation of Spt6 impacts its interactions with other proteins, and whether similar mechanisms exist in other organisms, offering new insights into the fundamental processes that govern life.

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This article is based on research published under:

DOI-LINK: 10.1016/j.celrep.2018.11.089, Alternate LINK

Title: Casein Kinase Ii Phosphorylation Of Spt6 Enforces Transcriptional Fidelity By Maintaining Spn1-Spt6 Interaction

Subject: General Biochemistry, Genetics and Molecular Biology

Journal: Cell Reports

Publisher: Elsevier BV

Authors: Raghuvar Dronamraju, Jenny L. Kerschner, Sarah A. Peck, Austin J. Hepperla, Alexander T. Adams, Katlyn D. Hughes, Sadia Aslam, Andrew R. Yoblinski, Ian J. Davis, Amber L. Mosley, Brian D. Strahl

Published: 2018-12-01

Everything You Need To Know

What is Spt6, and what role does it play in transcription?

Spt6 is a histone chaperone that plays a critical role during transcription. It associates with RNA polymerase II (RNAPII) and deposits nucleosomes in the wake of transcription. Nucleosomes are the structural units of DNA packaging. Spt6 ensures the DNA is properly organized after RNAPII has passed, which is essential for maintaining genomic stability and preventing errors in gene expression. Without Spt6, the DNA structure would be compromised, potentially leading to incorrect gene transcription.

Why is casein kinase II (CKII) phosphorylation of Spt6 so important?

Casein kinase II (CKII) phosphorylation of Spt6 is important because it prevents errors in gene expression and maintains genomic stability. Specifically, CKII phosphorylation of Spt6 ensures nucleosome occupancy at the 5' ends of genes, which prevents aberrant antisense transcription and enforces transcriptional directionality. This modification of Spt6 by CKII is a key regulatory step that ensures genes are read correctly. Without CKII phosphorylation, the risk of producing non-functional or harmful RNA molecules increases.

What is 'aberrant antisense transcription', and why is it a problem?

Aberrant antisense transcription refers to the incorrect reading of genes in the wrong direction, leading to the production of non-functional or harmful RNA molecules. This is problematic because it disrupts the normal flow of genetic information and can lead to cellular dysfunction. CKII phosphorylation of Spt6 is crucial in preventing this by ensuring that transcription starts at the correct location and proceeds in the correct direction. This directional control is essential for maintaining the integrity of the transcriptome and proteome.

How does CKII phosphorylation of Spt6 help maintain genomic stability?

Genomic stability is maintained through various mechanisms, including the precise control of transcription. CKII phosphorylation of Spt6 contributes to genomic stability by preventing inappropriate transcription, which could otherwise lead to the production of non-functional or harmful RNA molecules. By ensuring that genes are read correctly and in the proper direction, this phosphorylation event minimizes the risk of errors that could compromise the integrity of the genome. This maintains the fidelity of the genetic information passed on during cell division.

What is Spn1, and how does it interact with Spt6 in the context of transcription?

Spn1 is a protein that interacts with Spt6 and is important for chromatin remodeling. CKII phosphorylation of Spt6 facilitates the interaction between Spt6 and Spn1, which promotes nucleosome occupancy at gene 5' ends. This interaction ensures transcription accuracy and directionality. The precise mechanisms of how Spn1 facilitates chromatin remodeling with Spt6 may require further investigation but the initial step is enabled by Spt6 phosphorylation.