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

Nat Commun. 2020 Sep 22;11(1):4784. doi: 10.1038/s41467-020-18506-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA Breaks, Double-Stranded*
  • DNA Damage
  • DNA End-Joining Repair
  • DNA Ligase ATP / metabolism
  • DNA Repair
  • DNA-Binding Proteins / chemistry
  • DNA-Directed DNA Polymerase / chemistry*
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Protein Conformation


  • DNA-Binding Proteins
  • DNA
  • DNA polymerase mu
  • DNA-Directed DNA Polymerase
  • DNA Ligase ATP