Abstract
Protein arginine deimination leading to the non-coded amino acid citrulline remains a key question in the field of post-translational modifications ever since its discovery by Rogers and Simmonds in 1958. Citrullination is catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). Initially, increased citrullination was associated with autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, as well as other neurological disorders and multiple types of cancer. During the last decade, research efforts have focused on how citrullination contributes to disease pathogenesis by modulating epigenetic events, pluripotency, immunity and transcriptional regulation. However, our knowledge regarding the functional implications of citrullination remains quite limited, so we still do not completely understand its role in physiological and pathological conditions. Here, we review the recently discovered functions of PADI2-mediated citrullination of the C-terminal domain of RNA polymerase II in transcriptional regulation in breast cancer cells and the proposed mechanisms to reshape the transcription regulatory network that promotes cancer progression.
Highlights
Deimination or citrullination as first described in 1958 by Rogers and Simmonds is a post-translational conversion of peptidyl-arginine to non-coded peptidyl-citrulline catalyzed by Ca2+- dependent peptidyl arginine deiminase (PADI) enzymes [1,2,3,4]
We found that PADI2, but not the other PADI family members, citrullinates arginine1810 (Cit1810) in repeat 31 of the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAP2) [85]
Many elongation factors and kinases participate in controlling the RNAP2 transcription pause release, a mechanism that regulates the expression of many genes involved in cancer progression and metastasis, like cyclin dependent kinase 9 (CDK9), v-myc myelocytomatosis viral oncogene homolog (MYC), Jumonji domain containing 6 (JMJD6), arginine demethylase and lysine hydroxylase and BRD4 [112,113,114,115,116]
Summary
Deimination or citrullination as first described in 1958 by Rogers and Simmonds is a post-translational conversion of peptidyl-arginine to non-coded peptidyl-citrulline catalyzed by Ca2+- dependent peptidyl arginine deiminase (PADI) enzymes [1,2,3,4]. Despite the high homology among family members, the five PADI enzymes have definite features, which facilitates the regulation of several distinct cellular processes. This feature may explain why altered levels of citrullination are associated with different pathological conditions, including multiple cancers [4,15,35,36,37,38,39,40,41]. The authors had not investigated the PADI2 substrates in this mice model [43] These studies highlight the relevance of citrullination to propagate inflammatory microenvironment, most likely involved in cancer cells. One unresolved question is how the hypoxic conditions in growing tumors influence PADI activity and citrullination
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