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 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
24.01.2023
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| ISSN: | 1091-6490, 1091-6490 |
| Online Access: | Get more information |
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| 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 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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| AbstractList | 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.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. 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. |
| Author | Buoninfante, Olimpia Alessandra Mcgrath, Kathleen E Zwart, Wilbert Palis, James Prekovic, Stefan Huijbers, Ivo J Pilzecker, Bas Vivié, Judith von Lindern, Marieke van den Berk, Paul C M Jacobs, Heinz Song, Ji-Ying Philipsen, Sjaak Pritchard, Colin E J Spanjaard, Aldo de Groot, Daniël Ayidah, Matilda Beijersbergen, Roderick L Lieftink, Cor |
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| Keywords | erythropoiesis embryonic lethality hematopoietic stem cells DNA damage tolerance (DDT) DNA damage response (DDR) |
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| SubjectTerms | Animals DNA Damage DNA Repair DNA Replication Hematopoietic Stem Cells - metabolism Mammals - metabolism Proliferating Cell Nuclear Antigen - metabolism Ubiquitination |
| Title | Mammalian life depends on two distinct pathways of DNA damage tolerance |
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