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Analysis of diverse double-strand break synapsis with Polλ reveals basis for unique substrate specificity in nonhomologous end-joining

Author

Listed:
  • Andrea M. Kaminski

    (National Institutes of Health)

  • Kishore K. Chiruvella

    (University of North Carolina at Chapel Hill)

  • Dale A. Ramsden

    (University of North Carolina at Chapel Hill)

  • Katarzyna Bebenek

    (National Institutes of Health)

  • Thomas A. Kunkel

    (National Institutes of Health)

  • Lars C. Pedersen

    (National Institutes of Health)

Abstract

DNA double-strand breaks (DSBs) threaten genomic stability, since their persistence can lead to loss of critical genetic information, chromosomal translocations or rearrangements, and cell death. DSBs can be repaired through the nonhomologous end-joining pathway (NHEJ), which processes and ligates DNA ends efficiently to prevent or minimize sequence loss. Polymerase λ (Polλ), one of the Family X polymerases, fills sequence gaps of DSB substrates with a strict specificity for a base-paired primer terminus. There is little information regarding Polλ’s approach to engaging such substrates. We used in vitro polymerization and cell-based NHEJ assays to explore the contributions of conserved loop regions toward DSB substrate specificity and utilization. In addition, we present multiple crystal structures of Polλ in synapsis with varying biologically relevant DSB end configurations, revealing how key structural features and hydrogen bonding networks work in concert to stabilize these tenuous, potentially cytotoxic DNA lesions during NHEJ.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31278-4
    DOI: 10.1038/s41467-022-31278-4
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    References listed on IDEAS

    as
    1. Stephen P. Jackson & Jiri Bartek, 2009. "The DNA-damage response in human biology and disease," Nature, Nature, vol. 461(7267), pages 1071-1078, October.
    2. 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.
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