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 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 Dikic; Matthias S Leisegang; Ralf P Brandes

doi:10.1016/j.celrep.2022.111670

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 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 journal › Article › Academic › peer-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 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.

Original language	English
Article number	111670
Number of pages	24
Journal	Cell Reports
Volume	41
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2022.111670
Publication status	Published - 15 Nov 2022

Keywords

Phosphorylation
RNA, Long Noncoding/genetics
Endothelial Cells/metabolism
DNA/metabolism
Replication Protein A/genetics

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10.1016/j.celrep.2022.111670Licence: CC BY

Cite this

Oo, J. A., Pálfi, K., Warwick, T., Wittig, I., Prieto-Garcia, C., Matkovic, V., Tomašković, I., Boos, F., Izquierdo Ponce, J., Teichmann, T., Petriukov, K., Haydar, S., Maegdefessel, L., Wu, Z., Pham, M. D., Krishnan, J., Baker, A. H., Günther, S., Ulrich, H. D., ... Brandes, R. P. (2022). Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2. Cell Reports, 41(7), Article 111670. https://doi.org/10.1016/j.celrep.2022.111670

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title = "Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2",

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.",

keywords = "Phosphorylation, RNA, Long Noncoding/genetics, Endothelial Cells/metabolism, DNA/metabolism, Replication Protein A/genetics",

author = "Oo, {James A} and Katalin P{\'a}lfi and Timothy Warwick and Ilka Wittig and Cristian Prieto-Garcia and Vigor Matkovic and Ines Toma{\v s}kovi{\'c} and Frederike Boos and {Izquierdo Ponce}, Judit and Tom Teichmann and Kirill Petriukov and Shaza Haydar and Lars Maegdefessel and Zhiyuan Wu and Pham, {Minh Duc} and Jaya Krishnan and Baker, {Andrew H} and Stefan G{\"u}nther and Ulrich, {Helle D} and Ivan Dikic and Leisegang, {Matthias S} and Brandes, {Ralf P}",

year = "2022",

month = nov,

day = "15",

doi = "10.1016/j.celrep.2022.111670",

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volume = "41",

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Oo, JA, Pálfi, K, Warwick, T, Wittig, I, Prieto-Garcia, C, Matkovic, V, Tomašković, I, Boos, F, Izquierdo Ponce, J, Teichmann, T, Petriukov, K, Haydar, S, Maegdefessel, L, Wu, Z, Pham, MD, Krishnan, J, Baker, AH, Günther, S, Ulrich, HD, Dikic, I, Leisegang, MS & Brandes, RP 2022, 'Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2', Cell Reports, vol. 41, no. 7, 111670. https://doi.org/10.1016/j.celrep.2022.111670

TY - JOUR

T1 - Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2

AU - Oo, James A

AU - Pálfi, Katalin

AU - Warwick, Timothy

AU - Wittig, Ilka

AU - Prieto-Garcia, Cristian

AU - Matkovic, Vigor

AU - Tomašković, Ines

AU - Boos, Frederike

AU - Izquierdo Ponce, Judit

AU - Teichmann, Tom

AU - Petriukov, Kirill

AU - Haydar, Shaza

AU - Maegdefessel, Lars

AU - Wu, Zhiyuan

AU - Pham, Minh Duc

AU - Krishnan, Jaya

AU - Baker, Andrew H

AU - Günther, Stefan

AU - Ulrich, Helle D

AU - Dikic, Ivan

AU - Leisegang, Matthias S

AU - Brandes, Ralf P

PY - 2022/11/15

Y1 - 2022/11/15

N2 - 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.

AB - 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.

KW - Phosphorylation

KW - RNA, Long Noncoding/genetics

KW - Endothelial Cells/metabolism

KW - DNA/metabolism

KW - Replication Protein A/genetics

U2 - 10.1016/j.celrep.2022.111670

DO - 10.1016/j.celrep.2022.111670

M3 - Article

C2 - 36384122

SN - 2211-1247

VL - 41

JO - Cell Reports

JF - Cell Reports

IS - 7

M1 - 111670

ER -