Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of replication protein A2

James A. Oo, Katalin Pálfi, Timothy Warwick, Ilka Wittig, Cristian Prieto-Garcia, Vigor Matkovic, Ines Tomašković, Frederike Boos, Judit Izquierdo Ponce, Tom Teichmann, Kirill Petriukov, Shaza Haydar, Lars Maegdefessel, Zhiyuan Wu, Minh Duc Pham, Jaya Krishnan, Andrew H Baker, Stefan Günther, Helle D. Ulrich, Ivan DikicMatthias S Leisegang, Ralf P Brandes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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, either in response to 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.
Original languageEnglish
JournalCell Reports
DOIs
Publication statusPublished - 15 Nov 2022

Keywords

  • Long non-coding RNA
  • endothelial cells
  • replication protein A
  • quiescence
  • checkpoint control
  • Ataxia telangiectasia and Rad3-related

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