Investigating the Functional Implications of Arginine Citrullination
Dr Priyanka SHARMA
Tuesday, September 17th 2019 - 11 a.m.
- Auditorium, IGBMC
Hosted by Romeo RICCI
My talk will illustrate the molecular functions of one of the post-translational modification known as citrullination or deimination. During citrullination arginine residues converted to the non-coded amino acid citrulline, catalyzed by a family of tissue-specific vertebrate enzymes called peptidyl arginine deiminases (PADIs). Among the PADI enzyme family, PADI2 is the most frequently overexpressed in primary breast tumors, is upregulated in luminal breast cancer cell lines, and is also associated with diverse pathological disorders including skin, lung, ovarian and colon cancers, prion diseases and neurological diseases. I will present our recent finding in breast cancer cells that PADI2 citrullinates the arginine R1810 within repeat 31 of the C-terminal domain (CTD-cit1810) of the large subunit of RNA polymerase 2 (RNAP2). Depletion of PADI2 or loss of R1810 result 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 its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells. Very recently, we also find that PADI2 modulate breast cancer stem cells properties, suggesting its possible role in drug resistance. Given that PADI2 overexpression in cancer is associated with poor prognosis, selective inhibitors of PADI2 action on R1810 could provide suitable drug target to use as combinatorial therapy to improve patients care.