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Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining

Author

Listed:
  • Benjamin M. Stinson

    (Harvard Medical School
    Howard Hughes Medical Institute)

  • Sean M. Carney

    (Harvard Medical School)

  • Johannes C. Walter

    (Harvard Medical School
    Howard Hughes Medical Institute)

  • Joseph J. Loparo

    (Harvard Medical School)

Abstract

Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double-strand-break (DSB) repair, directly re-ligates broken DNA ends. Damaged DSB ends that cannot be immediately re-ligated are modified by NHEJ processing enzymes, including error-prone polymerases and nucleases, to enable ligation. However, DSB ends that are initially compatible for re-ligation are typically joined without end processing. As both ligation and end processing occur in the short-range (SR) synaptic complex that closely aligns DNA ends, it remains unclear how ligation of compatible ends is prioritized over end processing. In this study, we identify structural interactions of the NHEJ-specific DNA Ligase IV (Lig4) within the SR complex that prioritize ligation and promote NHEJ fidelity. Mutational analysis demonstrates that Lig4 must bind DNA ends to form the SR complex. Furthermore, single-molecule experiments show that a single Lig4 binds both DNA ends at the instant of SR synapsis. Thus, Lig4 is poised to ligate compatible ends upon initial formation of the SR complex before error-prone processing. Our results provide a molecular basis for the fidelity of NHEJ.

Suggested Citation

  • Benjamin M. Stinson & Sean M. Carney & Johannes C. Walter & Joseph J. Loparo, 2024. "Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45553-z
    DOI: 10.1038/s41467-024-45553-z
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    References listed on IDEAS

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    1. Andrea M. Kaminski & Percy P. Tumbale & Matthew J. Schellenberg & R. Scott Williams & Jason G. Williams & Thomas A. Kunkel & Lars C. Pedersen & Katarzyna Bebenek, 2018. "Structures of DNA-bound human ligase IV catalytic core reveal insights into substrate binding and catalysis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Crystal A. Waters & Natasha T. Strande & John M. Pryor & Christina N. Strom & Piotr Mieczkowski & Martin D. Burkhalter & Sehyun Oh & Bahjat F. Qaqish & Dominic T. Moore & Eric A. Hendrickson & Dale A., 2014. "The fidelity of the ligation step determines how ends are resolved during nonhomologous end joining," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
    3. Carlas S. Smith & Karina Jouravleva & Maximiliaan Huisman & Samson M. Jolly & Phillip D. Zamore & David Grunwald, 2019. "An automated Bayesian pipeline for rapid analysis of single-molecule binding data," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    4. Siyu Chen & Linda Lee & Tasmin Naila & Susan Fishbain & Annie Wang & Alan E. Tomkinson & Susan P. Lees-Miller & Yuan He, 2021. "Structural basis of long-range to short-range synaptic transition in NHEJ," Nature, Nature, vol. 593(7858), pages 294-298, May.
    5. John R. Walker & Richard A. Corpina & Jonathan Goldberg, 2001. "Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair," Nature, Nature, vol. 412(6847), pages 607-614, August.
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