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The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function

Telomeres use shelterin to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), repressing ataxia-telangiectasia, mutated (ATM) and ATM and Rad3-related (ATR) dependent DNA damage checkpoint responses. The MRE11 nuclease is thought to be essential for the resection o...

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Autores principales: Rai, Rekha, Gu, Peili, Broton, Cayla, Kumar-Sinha, Chandan, Chen, Yong, Chang, Sandy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001145/
https://www.ncbi.nlm.nih.gov/pubmed/31825846
http://dx.doi.org/10.1016/j.celrep.2019.11.012
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author Rai, Rekha
Gu, Peili
Broton, Cayla
Kumar-Sinha, Chandan
Chen, Yong
Chang, Sandy
author_facet Rai, Rekha
Gu, Peili
Broton, Cayla
Kumar-Sinha, Chandan
Chen, Yong
Chang, Sandy
author_sort Rai, Rekha
collection PubMed
description Telomeres use shelterin to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), repressing ataxia-telangiectasia, mutated (ATM) and ATM and Rad3-related (ATR) dependent DNA damage checkpoint responses. The MRE11 nuclease is thought to be essential for the resection of the 5′ C-strand to generate the microhomologies necessary for alternative non-homologous end joining (A-NHEJ) repair. In the present study, we uncover DNA damage signaling and repair pathways engaged by components of the replisome complex to repair dysfunctional telomeres. In cells lacking MRN, single-stranded telomeric overhangs devoid of POT1-TPP1 do not recruit replication protein A (RPA), ATR-interacting protein (ATRIP), and RAD 51. Rather, components of the replisome complex, including Claspin, Proliferating cell nuclear antigen (PCNA), and Downstream neighbor of SON (DONSON), initiate DNA-PK(cs)-mediated p-CHK1 activation and A-NHEJ repair. In addition, Claspin directly interacts with TRF2 and recruits EXO1 to newly replicated telomeres to promote 5′ end resection. Our data indicate that MRN is dispensable for the repair of dysfunctional telomeres lacking POT1-TPP1 and highlight the contributions of the replisome in telomere repair.
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spelling pubmed-70011452020-02-05 The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function Rai, Rekha Gu, Peili Broton, Cayla Kumar-Sinha, Chandan Chen, Yong Chang, Sandy Cell Rep Article Telomeres use shelterin to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), repressing ataxia-telangiectasia, mutated (ATM) and ATM and Rad3-related (ATR) dependent DNA damage checkpoint responses. The MRE11 nuclease is thought to be essential for the resection of the 5′ C-strand to generate the microhomologies necessary for alternative non-homologous end joining (A-NHEJ) repair. In the present study, we uncover DNA damage signaling and repair pathways engaged by components of the replisome complex to repair dysfunctional telomeres. In cells lacking MRN, single-stranded telomeric overhangs devoid of POT1-TPP1 do not recruit replication protein A (RPA), ATR-interacting protein (ATRIP), and RAD 51. Rather, components of the replisome complex, including Claspin, Proliferating cell nuclear antigen (PCNA), and Downstream neighbor of SON (DONSON), initiate DNA-PK(cs)-mediated p-CHK1 activation and A-NHEJ repair. In addition, Claspin directly interacts with TRF2 and recruits EXO1 to newly replicated telomeres to promote 5′ end resection. Our data indicate that MRN is dispensable for the repair of dysfunctional telomeres lacking POT1-TPP1 and highlight the contributions of the replisome in telomere repair. 2019-12-10 2019-12-10 /pmc/articles/PMC7001145/ /pubmed/31825846 http://dx.doi.org/10.1016/j.celrep.2019.11.012 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Rai, Rekha
Gu, Peili
Broton, Cayla
Kumar-Sinha, Chandan
Chen, Yong
Chang, Sandy
The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
title The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
title_full The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
title_fullStr The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
title_full_unstemmed The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
title_short The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
title_sort replisome mediates a-nhej repair of telomeres lacking pot1-tpp1 independently of mrn function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001145/
https://www.ncbi.nlm.nih.gov/pubmed/31825846
http://dx.doi.org/10.1016/j.celrep.2019.11.012
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