Structural basis of long-range to short-range synaptic transition in NHEJ

Siyu Chen, Linda Lee, Tasmin Naila, Susan Fishbain, Annie Wang, Alan E. Tomkinson, Susan P. Lees-Miller and Yuan He ()
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Siyu Chen: Northwestern University
Linda Lee: University of Calgary
Tasmin Naila: University of New Mexico
Susan Fishbain: Northwestern University
Annie Wang: Northwestern University
Alan E. Tomkinson: University of New Mexico
Susan P. Lees-Miller: University of Calgary
Yuan He: Northwestern University

Nature, 2021, vol. 593, issue 7858, 294-298

Abstract: Abstract DNA double-strand breaks (DSBs) are a highly cytotoxic form of DNA damage and the incorrect repair of DSBs is linked to carcinogenesis1,2. The conserved error-prone non-homologous end joining (NHEJ) pathway has a key role in determining the effects of DSB-inducing agents that are used to treat cancer as well as the generation of the diversity in antibodies and T cell receptors2,3. Here we applied single-particle cryo-electron microscopy to visualize two key DNA–protein complexes that are formed by human NHEJ factors. The Ku70/80 heterodimer (Ku), the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), DNA ligase IV (LigIV), XRCC4 and XLF form a long-range synaptic complex, in which the DNA ends are held approximately 115 Å apart. Two DNA end-bound subcomplexes comprising Ku and DNA-PKcs are linked by interactions between the DNA-PKcs subunits and a scaffold comprising LigIV, XRCC4, XLF, XRCC4 and LigIV. The relative orientation of the DNA-PKcs molecules suggests a mechanism for autophosphorylation in trans, which leads to the dissociation of DNA-PKcs and the transition into the short-range synaptic complex. Within this complex, the Ku-bound DNA ends are aligned for processing and ligation by the XLF-anchored scaffold, and a single catalytic domain of LigIV is stably associated with a nick between the two Ku molecules, which suggests that the joining of both strands of a DSB involves both LigIV molecules.

Date: 2021
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DOI: 10.1038/s41586-021-03458-7

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