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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Biological Sciences
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942833/
https://www.ncbi.nlm.nih.gov/pubmed/36669105
http://dx.doi.org/10.1073/pnas.2216055120
Descripción
Sumario: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.

Ejemplares similares