Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2
James A. Oo, Katalin Pálfi, Timothy Warwick, Ilka Wittig, Cristian Prieto‐Garcia, Vigor Matković, Ines Tomašković, Frederike Boos, Judit Izquierdo Ponce, Tom Teichmann, Kirill Petriukov, Shaza Haydar, Lars Mäegdefessel, Zhiyuan Wu, Duc Minh Pham, Jaya Krishnan, Andrew H. Baker, Stefan Günther, Helle D. Ulrich, Ivan Đikić, Matthias S. Leisegang, Ralf P. Brandes
Abstract
In healthy vessels, endothelial cells maintain a stable, differentiated, and growth-arrested phenotype for years. Upon injury, a rapid phenotypic switch facilitates proliferation to restore tissue perfusion. Here we report the identification of the endothelial cell-enriched long non-coding RNA (lncRNA) PCAT19, which contributes to the proliferative switch and acts as a safeguard for the endothelial genome. PCAT19 is enriched in confluent, quiescent endothelial cells and binds to the full replication protein A (RPA) complex in a DNA damage- and cell-cycle-related manner. Our results suggest that PCAT19 limits the phosphorylation of RPA2, primarily on the serine 33 (S33) residue, and thereby facilitates an appropriate DNA damage response while slowing cell cycle progression. Reduction in PCAT19 levels in response to either loss of cell contacts or knockdown promotes endothelial proliferation and angiogenesis. Collectively, PCAT19 acts as a dynamic guardian of the endothelial genome and facilitates rapid switching from quiescence to proliferation.