PCAT19 safeguards quiescent endothelial DNA by preventing uncontrolled phosphorylation of replication protein A2

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 noncoding RNA (lncRNA) PCAT19, which contributes to this process and acts as a safeguard for the endothelial genome during the quiescent phase. PCAT19 is enriched in confluent, quiescent endothelial cells. PCAT19 binds to the full replication protein A (RPA) complex in a DNA damage and cell cycle-related manner. PCAT19 limits phosphorylation of RPA2 on the serine 33 (S33) residue and thereby facilitates the DNA damage response at the expense of slower cell cycle progression. Reduction in PCAT19 levels, either in response to loss of cell contacts or knockdown, promoted endothelial proliferation and angiogenic function. Collectively, PCAT19 acts as a dynamic guardian of the endothelial genome, promotes cellular longevity and facilitates rapid switching to proliferation. RNA sequencing (n = 3) of human umbilical vein endothelial cells (HUVEC) treated with either control LNA gapmers or PCAT19 LNA gapmers, which knockdown PCAT19 expression.