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Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

Author

Listed:
  • Junyeop Lee

    (Seoul National University)

  • Keewon Sung

    (Seoul National University)

  • So Young Joo

    (Seoul National University)

  • Jun-Hyeon Jeong

    (Seoul National University)

  • Seong Keun Kim

    (Seoul National University)

  • Hyunsook Lee

    (Seoul National University)

Abstract

BRCA2-deficient cells precipitate telomere shortening upon collapse of stalled replication forks. Here, we report that the dynamic interaction between BRCA2 and telomeric G-quadruplex (G4), the non-canonical four-stranded secondary structure, underlies telomere replication homeostasis. We find that the OB-folds of BRCA2 binds to telomeric G4, which can be an obstacle during replication. We further demonstrate that BRCA2 associates with G-triplex (G3)-derived intermediates, which are likely to form during direct interconversion between parallel and non-parallel G4. Intriguingly, BRCA2 binding to G3 intermediates promoted RAD51 recruitment to the telomere G4. Furthermore, MRE11 resected G4-telomere, which was inhibited by BRCA2. Pathogenic mutations at the OB-folds abrogated the binding with telomere G4, indicating that the way BRCA2 associates with telomere is innate to its tumor suppressor activity. Collectively, we propose that BRCA2 binding to telomeric G4 remodels it and allows RAD51-mediated restart of the G4-driven replication fork stalling, simultaneously preventing MRE11-mediated breakdown of telomere.

Suggested Citation

  • Junyeop Lee & Keewon Sung & So Young Joo & Jun-Hyeon Jeong & Seong Keun Kim & Hyunsook Lee, 2022. "Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31156-z
    DOI: 10.1038/s41467-022-31156-z
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    References listed on IDEAS

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    1. Jennifer M. Mason & Yuen-Ling Chan & Ralph W. Weichselbaum & Douglas K. Bishop, 2019. "Non-enzymatic roles of human RAD51 at stalled replication forks," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    2. Lina Sieverling & Chen Hong & Sandra D. Koser & Philip Ginsbach & Kortine Kleinheinz & Barbara Hutter & Delia M. Braun & Isidro Cortés-Ciriano & Ruibin Xi & Rolf Kabbe & Peter J. Park & Roland Eils & , 2020. "Genomic footprints of activated telomere maintenance mechanisms in cancer," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    3. Gary N. Parkinson & Michael P. H. Lee & Stephen Neidle, 2002. "Crystal structure of parallel quadruplexes from human telomeric DNA," Nature, Nature, vol. 417(6891), pages 876-880, June.
    4. Ming Lei & Elaine R. Podell & Peter Baumann & Thomas R. Cech, 2003. "DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA," Nature, Nature, vol. 426(6963), pages 198-203, November.
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