A new checkpoint mechanism: gene transcription can be fine-tuned

Researchers from the Wistar Institute in Philadelphia and the Peter Macallum Cancer Center in Melbourne, Australia, say they have discovered a new checkpoint mechanism that can fine-tune gene transcription

A study (PP2A-Integrator-CDK9 axis can fine-tune transcription and can be used for cancer treatment) was published in? Cells are an integral part of the integrin complex, which connects protein phosphatase 2A (PP2A) to the transcription site, allowing It stops the activity of RNA polymerase II (RNAPII)

According to the scientists, the disruption of this mechanism leads to unrestricted gene transcription and is linked to cancer

"RNA polymerase II (RNAPII) gene expression is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints in the transcription cycle

PP2A can dynamically antagonize the phosphorylation of key CDK9 substrates, including DSIF and RNAPII-CTD

"These data show that the fine control of gene expression depends on the balance between kinase and phosphatase activities throughout the transcription cycle, a process that is dysregulated in cancer and can be used for treatment

Control gene transcription

A team led by Alessandro, Dr.

“Cancer is the result of changes in gene expression.

"We believe that our findings provide new insights into how gene expression is tightly controlled," Johnstone added

The transcription of RNAPII enzyme is carried out in several steps.

The research team discovered that a phosphatase called protein phosphatase 2A (PP2A) is involved in this regulatory balance

CDK9 is a kind of CDKs that activate RNAPII by promoting elongation.

The research team discovered that a component of Integrator, the central regulator of the transcription process, interacts with PP2A phosphatase, recruits it to the transcription site, counteracts the activity of CDK9 at the transcription site, and prevents transcription prolongation

The researchers then tested the hypothesis that targeting the PP2A-integrr-CDK9 axis in cancer by simultaneously blocking CDK9 and activating PP2A can provide therapeutic benefits in mouse models of leukemia and solid cancer

In summary, this study describes a new basic mechanism of gene expression regulation and demonstrates that CDK9 inhibition and PP2A activation can enhance the anticancer effect of preclinical models of solid and hematopoietic malignancies.