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NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres

Rekha Rai1, Chunyi Hu2, Cayla Broton1

  • 1Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA.

Molecular Cell
|February 21, 2017
PubMed

Insights

Telomere protection relies on TRF2, which prevents DNA damage signaling. NBS1 phosphorylation by CDK2 dictates whether telomeres undergo repair or protection, revealing a key mechanism in DNA repair pathway choice.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Telomeres protect chromosome ends from DNA damage sensors.
  • TRF2 (Telomere Repeat Binding Factor 2) is crucial for telomere end protection and repressing DNA damage responses.
  • The mechanism by which TRF2 prevents activation of the MRN complex at dysfunctional telomeres is not fully understood.

Purpose of the Study:

  • To elucidate how TRF2 prevents MRN complex activation at dysfunctional telomeres.
  • To investigate the role of NBS1 phosphorylation in telomere repair pathway choice.
  • To understand the structural basis of TRF2-NBS1 interaction.

Main Methods:

  • X-ray crystallography to determine the structure of the TRF2-NBS1 complex.
  • Biochemical assays to study protein interactions and phosphorylation.
  • Analysis of DNA repair pathways at telomeres.

Main Results:

  • The crystal structure revealed NBS1's YQLSP motif interacting with the TRF2 TRFH domain.
  • CDK2-mediated phosphorylation of NBS1 serine 432 dissociates NBS1 from TRF2.
  • Phosphorylated NBS1 promotes telomere protection, while de-phosphorylated NBS1 facilitates alternative NHEJ repair.

Conclusions:

  • NBS1 phosphorylation status is a critical determinant of repair pathway choice at dysfunctional telomeres.
  • The TRF2 TRFH domain plays a key role in orchestrating telomere end protection.
  • This study reveals a novel mechanism linking NBS1 phosphorylation to telomere maintenance and DNA repair.

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