28 Aug Icahn Mt.Sinai Study Identifies Two Switches That Regulate RNA Transcription in Cancer Cells
MedicalResearch.com Interview with:
Robert Fisher, MD, PhD
Professor of Oncological Sciences
Icahn School of Medicine at Mount Sinai
Member of The Tisch Cancer Institute
MedicalResearch.com: What is the background for this study?
Response: Gene transcription by RNA polymerase II underlies cellular identity, and cell fate decisions such as proliferation or death, and is regulated by enzymes that add phosphates (kinases) or remove them (phosphatases) from components of the transcription machinery. Here we define two kinase-phosphatase switches that regulate different steps of the transcription cycle in human cancer cells.
We raised antibodies specific for different phosphorylated states of a key elongation factor, Spt5, and used genomic analyses such as chromatin immunoprecipitation and sequencing (ChIP-seq) to monitor when these phosphorylations were added and removed, and by which kinases and phosphatases, respectively, as RNA polymerase II traversed genes in human cancer cells.
MedicalResearch.com: What are the main findings?
Response: Phosphorylation of two distinct sites on Spt5 are both placed by Cdk9 at or near the beginning of transcription elongation but removed by different phosphatases. One phosphorylation, which appears to control the rate of elongation, is removed by PP1 as transcription complexes near the ends of genes and may be needed for proper termination. The other appears to be needed to release RNA polymerase II paused near the transcription start site into rapid elongation, is refractory to PP1 but sensitive to PP4, and is retained in the termination zone, possibly because PP4 is excluded from that region. Both PP4 and PP1 are themselves inhibited in cells through phosphorylations placed by Cdk9, which might contribute to the switch-like properties of pause release and termination.
This study showed for the first time that a key transcriptional kinase, Cdk9, acts in opposition to two different phosphatases, PP4 and PP1, at the entry to and exit from the elongation phase of the transcription cycle.
MedicalResearch.com: What should readers take away from your report?
Response: The transcription cycle is governed by kinase-phosphatase circuits in which the kinases negatively regulate the phosphatases, to ensure switch-like transitions between different stages of transcription. Similar switches, involving some of the same phosphatases, have previously been implicated in the control of the cell division cycle.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: This study should lead to intensified investigation of the mechanisms that underlie switching between kinase and phosphatase activity during transcription, and how perturbations of those switches might influence specific gene expression events in normal cells and in diseases such as cancer. Kinases involved in transcription, such as Cdk7 and Cdk12, have recently emerged as anti-cancer drug targets; this study raises the possibility that Cdk9 and its opposing phosphatases, PP4 and PP1, might also be promising targets.
Parua, P.K., Kalan, S., Benjamin, B. et al. Distinct Cdk9-phosphatase switches act at the beginning and end of elongation by RNA polymerase II. Nat Commun 11, 4338 (2020). https://doi.org/10.1038/s41467-020-18173-6
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