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Maf1-dependent regulation of RNA pol III activity by chromatin associated kinases

Maf1 has been recently identified as an evolutionary conserved, general negative RNA Pol III regulator. In S. cerevisiae, Maf1 is essential for repressing transcription by RNA Pol III and functions to integrate the responses from multiple nutritional and stress signaling pathways that coordinately regulate ribosome and tRNA synthesis, via the target-of-rapamycin (TOR) pathway.

Similar results have been obtained in human cells, thus establishing Maf1 as a conserved global repressor of RNA Pol III transcription and as a putative tumour suppressor. Furthermore, Maf1 is an important mediator of nutrient-dependent growth, under control of the TOR pathway, and has been shown to control body size and developmental timing in Drosophila by modulating tRNA(i)Met synthesis and systemic insulin signaling. Since overexpression of tRNA(i)Met can also be sufficient to drive proliferation and oncogenic transformation, targeting specifically the RNA Pol III machinery might have therapeutic potential.

In the nucleus Maf1 phosphorylation state is actively regulated by the activity of the evolutionary conserved TOR kinase domain, part of the TORC1 complex and the Casein kinase 2 (CK2) complex. Strikingly, TORC1 and CK2 complexes has been found to be associated with 5S rRNA and tRNAs genes, where they interact directly with the RNA Pol III machinery and relieve its repression by phosphorylating Maf1 at specific serine and threonine residues.

CK2 is recruited at tRNA genes by interacting directly with the transcription factor TFIIIB, and this association is enhanced in absence of Maf1, especially under repressive conditions. Accordingly, the long-term goal of this research is to gain mechanistical insights into the regulation of RNA Pol III by Maf1 and upstream kinases, to understand their role in RNA Pol III activity modulation, as well as other cellular processes, which happen on chromatin at RNA Pol III genes.

Our recent structural investigation of the RNA Pol III-Maf1 complex by a combination of X-ray crystallography and cryo-EM unraveled the location of Maf1 binding on Pol III surface and the molecular basis of its repressive activity. We are now biochemically and structurally investigating the nature of the association of Maf1 and RNA Pol III, as well as the association of components of the RNA Pol III machineries with Maf1-dependendent upstream kinases.

Maf1-dependent regulation of RNA polymerase III activity by chromatin associated kinases

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Architecture of the RNA Pol III pre-initiation complex RNA polymerase III regulation by tumour suppressors and oncogenes Maf1-dependent regulation of RNA pol III activity by chromatin associated kinases