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Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation
BACKGROUND: Pds5 is an abundant HEAT-repeat-containing protein that binds to cohesin and mediates sister chromatid cohesion. In vertebrates, Pds5A and Pds5B are known to protect DNA replication fork, as their loss leads to DNA damage. Pds5 interacts directly with Wapl, to remove cohesin during mitos...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372117/ https://www.ncbi.nlm.nih.gov/pubmed/32760717 http://dx.doi.org/10.3389/fcell.2020.00531 |
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author | Al-Jomah, Naif Mukololo, Lubinda Anjum, Awais Al Madadha, Mohammed Patel, Raj |
author_facet | Al-Jomah, Naif Mukololo, Lubinda Anjum, Awais Al Madadha, Mohammed Patel, Raj |
author_sort | Al-Jomah, Naif |
collection | PubMed |
description | BACKGROUND: Pds5 is an abundant HEAT-repeat-containing protein that binds to cohesin and mediates sister chromatid cohesion. In vertebrates, Pds5A and Pds5B are known to protect DNA replication fork, as their loss leads to DNA damage. Pds5 interacts directly with Wapl, to remove cohesin during mitosis. AIM: To analyze the effects of the loss of Pds5 proteins-mediated DNA damage on the cell cycle checkpoints and to examine the possibility that Pds5 proteins have an overlapping function. METHODS: We first analyzed the cell cycle regulation of Pds5 proteins and defects in S-phase; DNA damage was confirmed after Pds5A/B knockdown. The activation of cell cycle checkpoints and apoptosis were examined by the level of p-Chk1(S317), MAD2 localization, and the level of pro-apoptotic markers, respectively. RESULTS: Pds5 proteins dissociated from chromatin in a stepwise manner, and their loss led to activation of pro-apoptotic markers associated with the phosphorylation of Chk1(S317) due to DNA damage. Depletion of either Pds5A or Pds5B alone increased Smc3 acetylation in perturbed cell cycle, while depletion of both proteins severely impaired Smc3 acetylation. Moreover, the loss of Pds5A/Pds5B activated the SAC in an ATR-Chk1-dependent manner and stabilized Wapl on chromatin. The depletion of Chk1 rescued the S-phase delay associated with Pds5 depletion and significantly increased mitotic catastrophe. CONCLUSION: Pds5A and Pds5B display overlapping functions in facilitating Smc3 acetylation. Somewhat paradoxically, they also have non-redundant functions in terms of cohesin removal due to the activated surveillance mechanism that leads to phosphorylation of Chk1(S317). |
format | Online Article Text |
id | pubmed-7372117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73721172020-08-04 Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation Al-Jomah, Naif Mukololo, Lubinda Anjum, Awais Al Madadha, Mohammed Patel, Raj Front Cell Dev Biol Cell and Developmental Biology BACKGROUND: Pds5 is an abundant HEAT-repeat-containing protein that binds to cohesin and mediates sister chromatid cohesion. In vertebrates, Pds5A and Pds5B are known to protect DNA replication fork, as their loss leads to DNA damage. Pds5 interacts directly with Wapl, to remove cohesin during mitosis. AIM: To analyze the effects of the loss of Pds5 proteins-mediated DNA damage on the cell cycle checkpoints and to examine the possibility that Pds5 proteins have an overlapping function. METHODS: We first analyzed the cell cycle regulation of Pds5 proteins and defects in S-phase; DNA damage was confirmed after Pds5A/B knockdown. The activation of cell cycle checkpoints and apoptosis were examined by the level of p-Chk1(S317), MAD2 localization, and the level of pro-apoptotic markers, respectively. RESULTS: Pds5 proteins dissociated from chromatin in a stepwise manner, and their loss led to activation of pro-apoptotic markers associated with the phosphorylation of Chk1(S317) due to DNA damage. Depletion of either Pds5A or Pds5B alone increased Smc3 acetylation in perturbed cell cycle, while depletion of both proteins severely impaired Smc3 acetylation. Moreover, the loss of Pds5A/Pds5B activated the SAC in an ATR-Chk1-dependent manner and stabilized Wapl on chromatin. The depletion of Chk1 rescued the S-phase delay associated with Pds5 depletion and significantly increased mitotic catastrophe. CONCLUSION: Pds5A and Pds5B display overlapping functions in facilitating Smc3 acetylation. Somewhat paradoxically, they also have non-redundant functions in terms of cohesin removal due to the activated surveillance mechanism that leads to phosphorylation of Chk1(S317). Frontiers Media S.A. 2020-07-14 /pmc/articles/PMC7372117/ /pubmed/32760717 http://dx.doi.org/10.3389/fcell.2020.00531 Text en Copyright © 2020 Al-Jomah, Mukololo, Anjum, Al Madadha and Patel. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Al-Jomah, Naif Mukololo, Lubinda Anjum, Awais Al Madadha, Mohammed Patel, Raj Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation |
title | Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation |
title_full | Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation |
title_fullStr | Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation |
title_full_unstemmed | Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation |
title_short | Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation |
title_sort | pds5a and pds5b display non-redundant functions in mitosis and their loss triggers chk1 activation |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372117/ https://www.ncbi.nlm.nih.gov/pubmed/32760717 http://dx.doi.org/10.3389/fcell.2020.00531 |
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