The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
Summary: 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 re...
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doaj-0f21ce0df63548b298e21688e96c06dc2020-11-25T01:19:56ZengElsevierCell Reports2211-12472019-12-01291137083725.e5The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN FunctionRekha Rai0Peili Gu1Cayla Broton2Chandan Kumar-Sinha3Yong Chen4Sandy Chang5Departments of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06520, USA; Corresponding authorDepartments of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06520, USADepartments of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06520, USA; Tri-Institutional MD/PhD Program, Weill Cornell Medical College, New York, NY 10065, USADepartment of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USANational Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, ChinaDepartments of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06520, USA; Corresponding authorSummary: 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-PKcs-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. : Rai et al. define roles for the DNA replisome components Claspin, PCNA, and DONSON in the sensing and repair of telomeres lacking POT1-TPP1. In cells lacking MRN, CPD initiates DNA-PKcs-mediated p-CHK1 activation and A-NHEJ repair. Claspin directly interacts with TRF2 and recruits EXO1 to promote 5′ C-strand end resection. Keywords: telomere, TRF2, POT1, DNA damage, A-NHEJ repair, replisome, MRE11-RAD50-NBS1http://www.sciencedirect.com/science/article/pii/S2211124719314834 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rekha Rai Peili Gu Cayla Broton Chandan Kumar-Sinha Yong Chen Sandy Chang |
spellingShingle |
Rekha Rai Peili Gu Cayla Broton Chandan Kumar-Sinha Yong Chen Sandy Chang The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function Cell Reports |
author_facet |
Rekha Rai Peili Gu Cayla Broton Chandan Kumar-Sinha Yong Chen Sandy Chang |
author_sort |
Rekha Rai |
title |
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_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_sort |
replisome mediates a-nhej repair of telomeres lacking pot1-tpp1 independently of mrn function |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2019-12-01 |
description |
Summary: 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-PKcs-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. : Rai et al. define roles for the DNA replisome components Claspin, PCNA, and DONSON in the sensing and repair of telomeres lacking POT1-TPP1. In cells lacking MRN, CPD initiates DNA-PKcs-mediated p-CHK1 activation and A-NHEJ repair. Claspin directly interacts with TRF2 and recruits EXO1 to promote 5′ C-strand end resection. Keywords: telomere, TRF2, POT1, DNA damage, A-NHEJ repair, replisome, MRE11-RAD50-NBS1 |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719314834 |
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