Time-lapse crystallography snapshots of a double-strand break repair polymerase in action

Joonas A. Jamsen, William A. Beard, Lars C. Pedersen, David D. Shock, Andrea F. Moon, Juno M. Krahn, Katarzyna Bebenek, Thomas A. Kunkel and Samuel H. Wilson ()
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Joonas A. Jamsen: National Institutes of Health
William A. Beard: National Institutes of Health
Lars C. Pedersen: National Institutes of Health
David D. Shock: National Institutes of Health
Andrea F. Moon: National Institutes of Health
Juno M. Krahn: National Institutes of Health
Katarzyna Bebenek: National Institutes of Health
Thomas A. Kunkel: National Institutes of Health
Samuel H. Wilson: National Institutes of Health

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract DNA polymerase (pol) μ is a DNA-dependent polymerase that incorporates nucleotides during gap-filling synthesis in the non-homologous end-joining pathway of double-strand break repair. Here we report time-lapse X-ray crystallography snapshots of catalytic events during gap-filling DNA synthesis by pol μ. Unique catalytic intermediates and active site conformational changes that underlie catalysis are uncovered, and a transient third (product) metal ion is observed in the product state. The product manganese coordinates phosphate oxygens of the inserted nucleotide and PPi. The product metal is not observed during DNA synthesis in the presence of magnesium. Kinetic analyses indicate that manganese increases the rate constant for deoxynucleoside 5′-triphosphate insertion compared to magnesium. The likely product stabilization role of the manganese product metal in pol μ is discussed. These observations provide insight on structural attributes of this X-family double-strand break repair polymerase that impact its biological function in genome maintenance.

Date: 2017
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DOI: 10.1038/s41467-017-00271-7

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