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Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration
How salamanders accomplish progenitor cell proliferation while faithfully maintaining genomic integrity and regenerative potential remains elusive. Here we found an innate DNA damage response mechanism that is evident during blastema proliferation (early- to late-bud) and studied its role during tis...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093111/ https://www.ncbi.nlm.nih.gov/pubmed/32142407 http://dx.doi.org/10.7554/eLife.51217 |
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author | Sousounis, Konstantinos Bryant, Donald M Martinez Fernandez, Jose Eddy, Samuel S Tsai, Stephanie L Gundberg, Gregory C Han, Jihee Courtemanche, Katharine Levin, Michael Whited, Jessica L |
author_facet | Sousounis, Konstantinos Bryant, Donald M Martinez Fernandez, Jose Eddy, Samuel S Tsai, Stephanie L Gundberg, Gregory C Han, Jihee Courtemanche, Katharine Levin, Michael Whited, Jessica L |
author_sort | Sousounis, Konstantinos |
collection | PubMed |
description | How salamanders accomplish progenitor cell proliferation while faithfully maintaining genomic integrity and regenerative potential remains elusive. Here we found an innate DNA damage response mechanism that is evident during blastema proliferation (early- to late-bud) and studied its role during tissue regeneration by ablating the function of one of its components, Eyes absent 2. In eya2 mutant axolotls, we found that DNA damage signaling through the H2AX histone variant was deregulated, especially within the proliferating progenitors during limb regeneration. Ultimately, cell cycle progression was impaired at the G1/S and G2/M transitions and regeneration rate was reduced. Similar data were acquired using acute pharmacological inhibition of the Eya2 phosphatase activity and the DNA damage checkpoint kinases Chk1 and Chk2 in wild-type axolotls. Together, our data indicate that highly-regenerative animals employ a robust DNA damage response pathway which involves regulation of H2AX phosphorylation via Eya2 to facilitate proper cell cycle progression upon injury. |
format | Online Article Text |
id | pubmed-7093111 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-70931112020-03-25 Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration Sousounis, Konstantinos Bryant, Donald M Martinez Fernandez, Jose Eddy, Samuel S Tsai, Stephanie L Gundberg, Gregory C Han, Jihee Courtemanche, Katharine Levin, Michael Whited, Jessica L eLife Developmental Biology How salamanders accomplish progenitor cell proliferation while faithfully maintaining genomic integrity and regenerative potential remains elusive. Here we found an innate DNA damage response mechanism that is evident during blastema proliferation (early- to late-bud) and studied its role during tissue regeneration by ablating the function of one of its components, Eyes absent 2. In eya2 mutant axolotls, we found that DNA damage signaling through the H2AX histone variant was deregulated, especially within the proliferating progenitors during limb regeneration. Ultimately, cell cycle progression was impaired at the G1/S and G2/M transitions and regeneration rate was reduced. Similar data were acquired using acute pharmacological inhibition of the Eya2 phosphatase activity and the DNA damage checkpoint kinases Chk1 and Chk2 in wild-type axolotls. Together, our data indicate that highly-regenerative animals employ a robust DNA damage response pathway which involves regulation of H2AX phosphorylation via Eya2 to facilitate proper cell cycle progression upon injury. eLife Sciences Publications, Ltd 2020-03-06 /pmc/articles/PMC7093111/ /pubmed/32142407 http://dx.doi.org/10.7554/eLife.51217 Text en © 2020, Sousounis et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Developmental Biology Sousounis, Konstantinos Bryant, Donald M Martinez Fernandez, Jose Eddy, Samuel S Tsai, Stephanie L Gundberg, Gregory C Han, Jihee Courtemanche, Katharine Levin, Michael Whited, Jessica L Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration |
title | Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration |
title_full | Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration |
title_fullStr | Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration |
title_full_unstemmed | Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration |
title_short | Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration |
title_sort | eya2 promotes cell cycle progression by regulating dna damage response during vertebrate limb regeneration |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093111/ https://www.ncbi.nlm.nih.gov/pubmed/32142407 http://dx.doi.org/10.7554/eLife.51217 |
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