Dual DNA and RNA Binding Helix-Turn-Helix Protein Regulates Phage Anti-CRISPR Expression

แนวคิดหลัก

A single helix-turn-helix (HTH) domain protein, Aca2, regulates phage anti-CRISPR (acr) gene expression through both transcriptional repression by DNA binding and translational inhibition by binding conserved RNA stem-loops.

บทคัดย่อ

The content discusses how a single helix-turn-helix (HTH) domain protein, Aca2, regulates the expression of phage anti-CRISPR (acr) genes through a dual mechanism.
First, Aca2 represses acr transcription by binding to DNA through its HTH domain. This transcriptional repression helps reduce the fitness costs associated with excessive acr expression.
Second, Aca2 also binds to conserved RNA stem-loop structures in acr mRNAs, inhibiting their translation by blocking ribosome access. This translational repression complements the transcriptional control, allowing Aca2 to fine-tune acr expression as the phage genome copies and acr mRNA levels increase during infection.
The cryo-electron microscopy structure of the Aca2-RNA complex reveals how the versatile HTH domain can specifically discriminate between DNA and RNA binding sites. This dual regulatory mechanism involving both DNA and RNA binding is found to be widespread in the Aca2 protein family, enabling effective CRISPR-Cas inhibition even as phage DNA replicates rapidly.
The content suggests that many more helix-turn-helix domain proteins may exhibit this ability to control gene expression through combined transcriptional and translational regulation by binding to both DNA and RNA.

สถิติ

The approximately 40 kDa Aca2-RNA complex was studied using cryo-electron microscopy.

คำพูด

"the HTH domain of the regulator Aca2, in addition to repressing Acr synthesis transcriptionally through DNA binding, inhibits translation of mRNAs by binding conserved RNA stem-loops and blocking ribosome access."
"These combined regulatory modes are widespread in the Aca2 family and facilitate CRISPR–Cas inhibition in the face of rapid phage DNA replication without toxic acr overexpression."

ข้อมูลเชิงลึกที่สำคัญจาก

Phage anti-CRISPR control by an RNA- and DNA-binding helix–turn–helix protein - Nature

by Nils Birkhol... ที่ www.nature.com 07-10-2024

https://www.nature.com/articles/s41586-024-07644-1

สอบถามเพิ่มเติม

How might this dual DNA and RNA binding mechanism in Aca2 proteins be exploited for therapeutic applications against phage infections?

The dual DNA and RNA binding mechanism in Aca2 proteins presents a promising avenue for developing novel therapeutic strategies against phage infections. By targeting the specific interactions between Aca2 and both DNA and RNA, researchers could potentially design small molecules or peptides that disrupt these binding events. This disruption could lead to the upregulation of phage anti-CRISPR (acr) genes, thereby enhancing the host's defense mechanisms against phage invasion. Additionally, by understanding the structural basis of the Aca2-RNA complex through cryo-electron microscopy, scientists can design inhibitors that specifically block the translational inhibition of mRNAs by Aca2, further bolstering the host's ability to combat phage infections. Overall, leveraging the dual regulatory functions of Aca2 proteins could pave the way for the development of innovative antiviral therapies targeting phage infections.

What other cellular processes or pathways might be regulated by helix-turn-helix domain proteins through a similar combined transcriptional and translational control strategy?

Helix-turn-helix (HTH) domain proteins, known for their role in gene regulation, could potentially regulate various cellular processes or pathways through a similar combined transcriptional and translational control strategy observed in Aca2 proteins. One such process could be the regulation of immune responses, where HTH domain proteins might modulate the expression of immune-related genes at both the transcriptional and translational levels to fine-tune the immune response. Additionally, HTH domain proteins could be involved in developmental pathways, where they regulate the expression of key developmental genes through a dual mechanism to ensure precise spatiotemporal control. Moreover, in stress response pathways, HTH domain proteins may coordinate the cellular response by simultaneously controlling gene expression and protein synthesis in reaction to environmental stimuli. The versatility of HTH domain proteins suggests that they could play a crucial role in orchestrating a wide range of cellular processes through a combined transcriptional and translational control strategy.

Given the ubiquity of helix-turn-helix domains, could this mode of regulation be extended beyond just phage-bacteria interactions to other host-pathogen systems or even broader cellular regulatory networks?

The widespread presence of helix-turn-helix (HTH) domains across diverse organisms suggests that the mode of regulation observed in Aca2 proteins could indeed be extended beyond phage-bacteria interactions to other host-pathogen systems and broader cellular regulatory networks. In host-pathogen interactions, HTH domain proteins may play a pivotal role in regulating the expression of defense genes against various pathogens, not limited to bacteriophages. For instance, in viral infections, HTH domain proteins could modulate the host's antiviral response by controlling gene expression and translation of viral RNA. Furthermore, in eukaryotic systems, HTH domain proteins might participate in intricate regulatory networks governing fundamental cellular processes such as cell cycle progression, differentiation, and apoptosis. The ability of HTH domain proteins to integrate transcriptional and translational control mechanisms makes them versatile regulators that could influence a wide array of biological pathways beyond phage-bacteria interactions.