Genes contain all the information needed for the functioning of cells, tissues, and organs in our body. Gene expression, meaning when and how are the genes being read and executed, is thoroughly regulated like an assembly line with several things happening one after another.

Researchers have discovered a new step in this line, which controls the expression of some genes with an important role in cancer. "We observed that breast cancer cells need a particular modification to express a set of genes required for cellular proliferation and tumor progression," explains first author of the paper. "This modification allows the enzyme RNA polymerase II to overcome a pausing barrier and to continue to transcribe these genes," adds the author.

Cancer cells are willing to quickly proliferate so, genes involved in cell division and proliferation are really active and usually highly expressed. Such a precise and meticulous machinery involves many different molecules to properly function. In this case, when all the machinery to express proliferation genes is ready, it still has to wait for a particular modification to go. As in race when runners are asked to be ready, set and go. Here, the polymerase is also ready and set but still needs a final modification to cross the barrier for transcription and go.

"Deciphering every single step and all actors involved in this process is an important achievement in terms of fundamental science. We are now able to better understand how an intricate mechanism of gene regulation actually works and this might be a new target for clinical researchers to study novel therapies for certain types of cancer," states the principal investigator in this work.

The work, which has been published in Molecular Cell, describes a novel modification of in the Carboxyl terminal domain (CTD) of RNA Polymerase II, namely the de-imination of an arginine, and its conversion to citrulline by the enzyme peptidyl arginine deiminase 2 (PADI2), which allows the polymerase to transcribe genes relevant for cancer cell growth.

Among PADI family members, only PADI2 citrullinates R1810 (Cit1810) at repeat 31 of the CTD. Depletion of PADI2 or loss of R1810 results in accumulation of RNAP2 at transcription start sites, reduced gene expression, and inhibition of cell proliferation. Cit1810 is needed for interaction with the P-TEFb (positive transcription elongation factor b) kinase complex and for its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells.

"Most chemo-therapies are oriented at blocking the activity of enzymes, but we know that PADI2 participates in many different processes involving the nervous system, immune response and inflammation, among others. Thus, inhibiting PADI2 would have multiple side effects. Our results make it possible to target just the particular action of PADI2 on RNA polymerase needed for tumor progression without globally blocking the enzyme," explains the PI.

https://www.crg.eu/en/news/ready-set-go-crossing-barrier

https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30848-7?_