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Dr. Priyanka Sharma - Transcription regulation by arginine citrullination: molecular mechanism and possible consequences in cancer

 

Priyanka Sharma

Institut de Recherche en Cancérologie, Montpellier

Transcription regulation by arginine citrullination: molecular mechanism and possible consequences in cancer

Transcription regulation by RNA Polymerase 2 (RNAP2) guided by tissue-specific transcription factors determines the cell identity and function. The low complexity carboxyl-terminal domain (CTD) of the large subunit of RNAP2 is considered a landing platform to recruit a variety of protein complexes to modify the chromatin and process the nascent transcripts. Thus, identifying the molecular mechanisms that regulate the recruitment of protein complexes to the RNAP2 complex is mandatory for understanding cell function. The acquisition of the post-translational marks on the CTD of RNAP2 is known to affect the outcome of co-transcriptional, as well as post-transcriptional splicing events coupling with chromatin factors.

 

Our lab is focused to investigate the function of one of the post-translational conversions namely arginine citrullination in transcription machinery regulation and its role in cancer biology. Citrullination is the modification of arginine to the non-coded amino acid citrulline, catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). PADI2 is widely expressed among the family members and regulates several cellular processes associated with tumor progression. Importantly, PADI2 is intricately involved in the progression of several tumors and also drug resistance, while the underlying functional mechanism is not yet understood. We found that peptidyl arginine deiminases (PADI2) specifically citrullinates the RNAP2 to maintain the cell identity. Our work demonstrated that the conversion of R1810 to citrulline (R>Cit1810) at CTD is crucial for RNAP2 to overcome the pausing barrier close to the transcription start site allowing the efficient transcription of highly expressed genes needed for cellular proliferation. Notably, Cit1810 of RNAP2 is required to overcome pausing and facilitate transcription elongation of genes needed for cell proliferation and cell identity. I will discuss the spectrum of function of PADI2-mediated citrullination and its coordination with transcriptional events, which could give functional insights into its regulation in cancer.

Selected references

  • Miguel Beato, Priyanka Sharma (2020). Peptidyl Arginine Deiminase 2 (PADI2)-mediated Arginine Citrullination modulates Transcription in Cancer. International Journal of Molecular Science 21; 1351
  • Priyanka Sharma, Antonios Lioutas, Narcis Fernandez-Fuentes, Javier Quilez, José Carbonell-Caballero, Roni H G Wright, Chiara Di Vona, François Le Dily, Roland Schüller, Dirk Eick, Baldomero Oliva, Miguel Beato (2019). Arginine citrullination at the C-terminal domain controls RNA Polymerase II transcription. Molecular Cell 73; 84-96
  • Arun Kumar, Priyanka Sharma, Mercè Gomar-Alba, Zhanna Shcheprova, Anne Daulny, Trinidad Sanmartín, Irene Matucci, Charlotta Funaya, Miguel Beato, Manuel Mendoza (2018). Daughter-Cell-specific modulation of nuclear pore complexes controls cell cycle entry during asymmetric division. Nature Cell Biology 4; 432- 442
  • Priyanka Sharma, Saliha Azebi, Patrick England, Tove Christensen, Anné Møller-Larsen, Thor Petersen, Eric Batsché, Christian Muchardt (2012). Citrullination of histone H3 interferes with HP1-mediated transcriptional repression. PLoS Genetics 8; e1002934

Contact: Olivier Neyrolles (Olivier.Neyrolles@ipbs.fr)

Link to attend the seminar:

30 Jun

11:00 - 12:00

Seminar room - IPBS | Hybrid conference