Mammalian life depends on two distinct pathways of DNA damage tolerance
Buoninfante, Olimpia Alessandra; Pilzecker, Bas; Spanjaard, Aldo; de Groot, Daniël; Prekovic, Stefan; Song, Ji-Ying; Lieftink, Cor; Ayidah, Matilda; Pritchard, Colin E J; Vivié, Judith; Mcgrath, Kathleen E; Huijbers, Ivo J; Philipsen, Sjaak; von Lindern, Marieke; Zwart, Wilbert; Beijersbergen, Roderick L; Palis, James; van den Berk, Paul C M; Jacobs, Heinz
(2023) Proceedings of the National Academy of Sciences of the United States of America, volume 120, issue 4
(Article)
Abstract
DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation
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of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.
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Keywords: Animals, DDT, DNA Damage, DNA Repair, DNA Replication, Hematopoietic Stem Cells/metabolism, Mammals/metabolism, Proliferating Cell Nuclear Antigen/metabolism, Ubiquitination, DNA damage tolerance (DDT), DNA damage response (DDR), embryonic lethality, erythropoiesis, hematopoietic stem cells, General, Journal Article
ISSN: 1091-6490
Publisher: National Academy of Sciences
Note: Funding Information: We like to thank N. Wit and F. Alemdehy for comments on the manuscript, members of the FACS facility for assistance during sorting and flow cytometric analysis, the biotechnical staff of the Netherlands Cancer Institute - Antoni van Leeuwenhoek Mouse Clinic for Cancer and Aging (MCCA) for biotechnical support, C. Göbel for help with ChIP-Seq experiments, and all the members of mouse facility for assistance in maintenance of mice. Portions of this work were developed from the doctoral dissertation of O.A.B. Publisher Copyright: Copyright © 2023 the Author(s).
(Peer reviewed)
