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MYBL2 and ATM suppress replication stress in pluripotent stem cells
Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR‐dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be different due to alterations in cell cycle p...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097389/ https://www.ncbi.nlm.nih.gov/pubmed/33779025 http://dx.doi.org/10.15252/embr.202051120 |
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author | Blakemore, Daniel Vilaplana‐Lopera, Nuria Almaghrabi, Ruba Gonzalez, Elena Moya, Miriam Ward, Carl Murphy, George Gambus, Agnieszka Petermann, Eva Stewart, Grant S García, Paloma |
author_facet | Blakemore, Daniel Vilaplana‐Lopera, Nuria Almaghrabi, Ruba Gonzalez, Elena Moya, Miriam Ward, Carl Murphy, George Gambus, Agnieszka Petermann, Eva Stewart, Grant S García, Paloma |
author_sort | Blakemore, Daniel |
collection | PubMed |
description | Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR‐dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be different due to alterations in cell cycle phase length. The transcription factor MYBL2, which is implicated in cell cycle regulation, is expressed a hundred to a thousand‐fold more in ESCs compared with somatic cells. Here we show that MYBL2 activates ATM and suppresses replication stress in ESCs. Consequently, loss of MYBL2 or inhibition of ATM or Mre11 in ESCs results in replication fork slowing, increased fork stalling and elevated origin firing. Additionally, we demonstrate that inhibition of CDC7 activity rescues replication stress induced by MYBL2 loss and ATM inhibition, suggesting that uncontrolled new origin firing may underlie the replication stress phenotype resulting from loss/inhibition of MYBL2 and ATM. Overall, our study proposes that in addition to ATR, a MYBL2‐MRN‐ATM replication stress response pathway functions in ESCs to control DNA replication initiation and prevent genome instability. |
format | Online Article Text |
id | pubmed-8097389 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80973892021-05-14 MYBL2 and ATM suppress replication stress in pluripotent stem cells Blakemore, Daniel Vilaplana‐Lopera, Nuria Almaghrabi, Ruba Gonzalez, Elena Moya, Miriam Ward, Carl Murphy, George Gambus, Agnieszka Petermann, Eva Stewart, Grant S García, Paloma EMBO Rep Articles Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR‐dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be different due to alterations in cell cycle phase length. The transcription factor MYBL2, which is implicated in cell cycle regulation, is expressed a hundred to a thousand‐fold more in ESCs compared with somatic cells. Here we show that MYBL2 activates ATM and suppresses replication stress in ESCs. Consequently, loss of MYBL2 or inhibition of ATM or Mre11 in ESCs results in replication fork slowing, increased fork stalling and elevated origin firing. Additionally, we demonstrate that inhibition of CDC7 activity rescues replication stress induced by MYBL2 loss and ATM inhibition, suggesting that uncontrolled new origin firing may underlie the replication stress phenotype resulting from loss/inhibition of MYBL2 and ATM. Overall, our study proposes that in addition to ATR, a MYBL2‐MRN‐ATM replication stress response pathway functions in ESCs to control DNA replication initiation and prevent genome instability. John Wiley and Sons Inc. 2021-03-28 2021-05-05 /pmc/articles/PMC8097389/ /pubmed/33779025 http://dx.doi.org/10.15252/embr.202051120 Text en ©2021 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Blakemore, Daniel Vilaplana‐Lopera, Nuria Almaghrabi, Ruba Gonzalez, Elena Moya, Miriam Ward, Carl Murphy, George Gambus, Agnieszka Petermann, Eva Stewart, Grant S García, Paloma MYBL2 and ATM suppress replication stress in pluripotent stem cells |
title | MYBL2 and ATM suppress replication stress in pluripotent stem cells |
title_full | MYBL2 and ATM suppress replication stress in pluripotent stem cells |
title_fullStr | MYBL2 and ATM suppress replication stress in pluripotent stem cells |
title_full_unstemmed | MYBL2 and ATM suppress replication stress in pluripotent stem cells |
title_short | MYBL2 and ATM suppress replication stress in pluripotent stem cells |
title_sort | mybl2 and atm suppress replication stress in pluripotent stem cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097389/ https://www.ncbi.nlm.nih.gov/pubmed/33779025 http://dx.doi.org/10.15252/embr.202051120 |
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