The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function
| Autor: | Chandan Kumar-Sinha, Rekha Rai, Cayla Broton, Yong Chen, Sandy Chang, Peili Gu |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
DNA End-Joining Repair DNA damage Telomere-Binding Proteins Cell Cycle Proteins DNA-Directed DNA Polymerase Biology Aminopeptidases General Biochemistry Genetics and Molecular Biology Shelterin Complex Article 03 medical and health sciences Mice 0302 clinical medicine Multienzyme Complexes Cell Line Tumor Proliferating Cell Nuclear Antigen Animals Humans Telomeric Repeat Binding Protein 2 Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Replication protein A lcsh:QH301-705.5 Cells Cultured Adaptor Proteins Signal Transducing Nuclease MRE11 Homologue Protein G2-M DNA damage checkpoint Telomere Shelterin Proliferating cell nuclear antigen Cell biology Acid Anhydride Hydrolases DNA-Binding Proteins enzymes and coenzymes (carbohydrates) 030104 developmental biology DNA Repair Enzymes Exodeoxyribonucleases HEK293 Cells lcsh:Biology (General) Checkpoint Kinase 1 biology.protein Replisome Serine Proteases 030217 neurology & neurosurgery |
| Zdroj: | Cell reports Cell Reports, Vol 29, Iss 11, Pp 3708-3725.e5 (2019) |
| ISSN: | 2211-1247 |
| Popis: | 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. Graphical Abstract In Brief 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. |
| Databáze: | OpenAIRE |
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