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ATRIP protects progenitor cells against DNA damage in vivo
The maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591577/ https://www.ncbi.nlm.nih.gov/pubmed/33110058 http://dx.doi.org/10.1038/s41419-020-03090-9 |
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author | Matos-Rodrigues, Gabriel E. Grigaravicius, Paulius Lopez, Bernard S. Hofmann, Thomas Frappart, Pierre-Olivier Martins, Rodrigo A. P. |
author_facet | Matos-Rodrigues, Gabriel E. Grigaravicius, Paulius Lopez, Bernard S. Hofmann, Thomas Frappart, Pierre-Olivier Martins, Rodrigo A. P. |
author_sort | Matos-Rodrigues, Gabriel E. |
collection | PubMed |
description | The maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cells in vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation of Atrip in progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death. Trp53 inactivation in Atrip-deficient progenitor cells rescued apoptosis, but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication. |
format | Online Article Text |
id | pubmed-7591577 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75915772020-10-29 ATRIP protects progenitor cells against DNA damage in vivo Matos-Rodrigues, Gabriel E. Grigaravicius, Paulius Lopez, Bernard S. Hofmann, Thomas Frappart, Pierre-Olivier Martins, Rodrigo A. P. Cell Death Dis Article The maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cells in vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation of Atrip in progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death. Trp53 inactivation in Atrip-deficient progenitor cells rescued apoptosis, but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication. Nature Publishing Group UK 2020-10-28 /pmc/articles/PMC7591577/ /pubmed/33110058 http://dx.doi.org/10.1038/s41419-020-03090-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Matos-Rodrigues, Gabriel E. Grigaravicius, Paulius Lopez, Bernard S. Hofmann, Thomas Frappart, Pierre-Olivier Martins, Rodrigo A. P. ATRIP protects progenitor cells against DNA damage in vivo |
title | ATRIP protects progenitor cells against DNA damage in vivo |
title_full | ATRIP protects progenitor cells against DNA damage in vivo |
title_fullStr | ATRIP protects progenitor cells against DNA damage in vivo |
title_full_unstemmed | ATRIP protects progenitor cells against DNA damage in vivo |
title_short | ATRIP protects progenitor cells against DNA damage in vivo |
title_sort | atrip protects progenitor cells against dna damage in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591577/ https://www.ncbi.nlm.nih.gov/pubmed/33110058 http://dx.doi.org/10.1038/s41419-020-03090-9 |
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