Journal
MOLECULAR CELL
Volume 61, Issue 6, Pages 850-858Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.02.010
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Funding
- National Science Foundation Graduate Research Fellowship
- National Institutes of Health [R01GM115487]
- Stewart Trust
- Department of Defense [BC120436]
- Howard Hughes Medical Institute
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Repair of DNA double-strand breaks (DSBs) is essential for genomic stability. The most common DSB repair mechanism in human cells, non-homologous end joining (NHEJ), rejoins broken DNA ends by direct ligation. It remains unclear how components of the NHEJ machinery assemble a synaptic complex that bridges DNA ends. Here, we use single-molecule imaging in a vertebrate cell-free extract to show that synapsis of DNA ends occurs in at least two stages that are controlled by different NHEJ factors. DNA ends are initially tethered in a long-range complex whose formation requires the Ku70/ 80 heterodimer and the DNA-dependent protein kinase catalytic subunit. The ends are then closely aligned, which requires XLF, a non-catalytic function of XRCC4-LIG4, and DNA-PK activity. These results reveal a structural transition in the synaptic complex that governs alignment of DNA ends. Our approach provides a means of studying physiological DNA DSB repair at single-molecule resolution.
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