AI Article Synopsis
- Telomeres use the protein TRF2 to shield chromosome ends from DNA damage sensors like MRN, blocking certain DNA repair responses.
- The study reveals that the phosphorylation of the NBS1 protein is key in deciding how dysfunctional telomeres get repaired.
- The crystal structure of the TRF2-NBS1 complex reveals that specific interactions between TRF2 and NBS1, along with the phosphorylation state of NBS1, influence whether a cell uses different repair pathways for telomeres.
Article Abstract
Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. The crystal structure of the TRF2-NBS1 complex at 3.0 Å resolution shows that the NBS1 YQLSP motif interacts specifically with the TRF2 domain. Phosphorylation of NBS1 serine 432 by CDK2 in S/G2 dissociates NBS1 from TRF2, promoting TRF2-Apollo/SNM1B complex formation and the protection of leading-strand telomeres. Classical-NHEJ-mediated repair of telomeres lacking TRF2 requires phosphorylated NBS1 to activate ATM, while interaction of de-phosphorylated NBS1 with TRF2 promotes alternative-NHEJ repair of telomeres lacking POT1-TPP1. Our work advances understanding of how the TRF2 domain orchestrates telomere end protection and reveals how the phosphorylation status of the NBS1 dictates repair pathway choice of dysfunctional telomeres.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639704 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2017.01.016 | DOI Listing |
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