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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...

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Autores principales: Blakemore, Daniel, Vilaplana‐Lopera, Nuria, Almaghrabi, Ruba, Gonzalez, Elena, Moya, Miriam, Ward, Carl, Murphy, George, Gambus, Agnieszka, Petermann, Eva, Stewart, Grant S, García, Paloma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
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.
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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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