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Structural snapshots of human DNA polymerase μ engaged on a DNA double-strand break

Author

Listed:
  • Andrea M. Kaminski

    (National Institutes of Health)

  • John M. Pryor

    (University of North Carolina at Chapel Hill, 32-046 Lineberger Comprehensive Cancer Center)

  • Dale A. Ramsden

    (University of North Carolina at Chapel Hill, 32-046 Lineberger Comprehensive Cancer Center)

  • Thomas A. Kunkel

    (National Institutes of Health)

  • Lars C. Pedersen

    (National Institutes of Health)

  • Katarzyna Bebenek

    (National Institutes of Health)

Abstract

Genomic integrity is threatened by cytotoxic DNA double-strand breaks (DSBs), which must be resolved efficiently to prevent sequence loss, chromosomal rearrangements/translocations, or cell death. Polymerase μ (Polμ) participates in DSB repair via the nonhomologous end-joining (NHEJ) pathway, by filling small sequence gaps in broken ends to create substrates ultimately ligatable by DNA Ligase IV. Here we present structures of human Polμ engaging a DSB substrate. Synapsis is mediated solely by Polμ, facilitated by single-nucleotide homology at the break site, wherein both ends of the discontinuous template strand are stabilized by a hydrogen bonding network. The active site in the quaternary Pol μ complex is poised for catalysis and nucleotide incoporation proceeds in crystallo. These structures demonstrate that Polμ may address complementary DSB substrates during NHEJ in a manner indistinguishable from single-strand breaks.

Suggested Citation

  • Andrea M. Kaminski & John M. Pryor & Dale A. Ramsden & Thomas A. Kunkel & Lars C. Pedersen & Katarzyna Bebenek, 2020. "Structural snapshots of human DNA polymerase μ engaged on a DNA double-strand break," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18506-5
    DOI: 10.1038/s41467-020-18506-5
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    Cited by:

    1. Andrea M. Kaminski & Kishore K. Chiruvella & Dale A. Ramsden & Katarzyna Bebenek & Thomas A. Kunkel & Lars C. Pedersen, 2022. "Analysis of diverse double-strand break synapsis with Polλ reveals basis for unique substrate specificity in nonhomologous end-joining," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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