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POLR1D, a shared subunit of RNA polymerase I and III, modulates mTORC1 activity

Neuton Gorjão¹, Lukasz S Borowski², Roman J Szczesny¹

¹Institute of Biochemistry and Biophysics Polish Academy of Sciences, ul. Pawińskiego 5a, 02-106 Warsaw, Poland.

Biochimica Et Biophysica Acta. Molecular Cell Research

|April 13, 2025

Abstract:

The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial nutrient sensor and a major regulator of cell growth and proliferation. While mTORC1 activity is frequently upregulated in cancer, the mechanisms regulating mTORC1 are not fully understood. POLR1D, a shared subunit of RNA polymerases I and III, is often upregulated in colorectal cancer (CRC) and mutated in Treacher-Collins syndrome. POLR1D, together with its binding partner POLR1C, forms a dimer that is believed to initiate the assembly of the multisubunit RNA polymerases I and III. Our data reveal an unexpected link between POLR1D and mTORC1 signalling. We found that the overproduction of POLR1D in human cells stimulates mTORC1 activity. In contrast, the downregulation of POLR1D leads to the repression of the mTORC1 pathway. Additionally, we demonstrate that a pool of POLR1D localises to the cytoplasm and interacts with the mTORC1 regulator RAGA and RAPTOR. Furthermore, POLR1D enhances the interaction between RAPTOR and RAGA and sustains mTORC1 activity under starvation conditions. We have identified a novel role for the RNA polymerase I/III subunit POLR1D in regulating mTORC1 signalling. Our findings suggest the existence of a new node in the already complex mTORC1 signalling network, where POLR1D functions to convey the cell's internal status, namely polymerase assembly, to this kinase.

Insights

The RNA polymerase subunit POLR1D unexpectedly regulates mTORC1 signaling. Overproducing POLR1D boosts mTORC1 activity, while its depletion represses it, revealing a new link in cell growth control.

Area of Science:

Cellular Biology
Molecular Biology
Cancer Research

Background:

Mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, frequently dysregulated in cancer.
The precise mechanisms governing mTORC1 regulation remain incompletely understood.
POLR1D, a subunit of RNA polymerases I and III, is implicated in colorectal cancer and Treacher-Collins syndrome.

Purpose of the Study:

To investigate the potential role of POLR1D in regulating mTORC1 signaling.
To elucidate the molecular mechanisms connecting POLR1D to mTORC1 pathway activity.

Main Methods:

Studied the effect of POLR1D overproduction and downregulation on mTORC1 activity in human cells.
Investigated the subcellular localization and interaction of POLR1D with mTORC1 components.
Assessed the impact of POLR1D on mTORC1 regulation under nutrient starvation.

Main Results:

POLR1D overproduction stimulates mTORC1 activity, whereas POLR1D downregulation represses it.
A fraction of POLR1D localizes to the cytoplasm and interacts with RAGA and RAPTOR, key mTORC1 regulators.
POLR1D enhances the RAPTOR-RAGA interaction and maintains mTORC1 activity during starvation.

Conclusions:

Identified a novel function for the RNA polymerase subunit POLR1D in regulating mTORC1 signaling.
POLR1D acts as a new regulatory node in the mTORC1 pathway, potentially linking polymerase assembly status to kinase activity.

Read full analysis

Keywords:

POLR1D RNA polymerase III mTORC1

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