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

Andrea M. Kaminski, John M. Pryor, Dale A. Ramsden, Thomas A. Kunkel, Lars C. Pedersen () and Katarzyna Bebenek
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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

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18506-5

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