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

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

doi:10.1038/s41467-020-18506-5

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

Journal Article · Tue Sep 22 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-18506-5· OSTI ID:1669125

^[1]; Pryor, John M. ^[2]; ^[2]; ^[1]; ^[1]; Bebenek, Katarzyna ^[1]

National Institutes of Health (NIH), Research Triangle Park, NC (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Contributing Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

OSTI ID:: 1669125

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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