Mammalian life depends on two distinct pathways of DNA damage tolerance

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 4; p. e2216055120
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 24.01.2023
Subjects:
Animals
DNA Damage
DNA Repair
DNA Replication
Hematopoietic Stem Cells - metabolism
Mammals - metabolism
Proliferating Cell Nuclear Antigen - metabolism
Ubiquitination
erythropoiesis
embryonic lethality
hematopoietic stem cells
DNA damage tolerance (DDT)
DNA damage response (DDR)
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary: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 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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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2216055120