C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains

Ragini Bhargava, Manbir Sandhu, Sanychen Muk, Gabriella Lee, Nagarajan Vaidehi and Jeremy M. Stark ()
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Ragini Bhargava: Beckman Research Institute of the City of Hope
Manbir Sandhu: Beckman Research Institute of the City of Hope
Sanychen Muk: Beckman Research Institute of the City of Hope
Gabriella Lee: Beckman Research Institute of the City of Hope
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope
Jeremy M. Stark: Beckman Research Institute of the City of Hope

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract To investigate the fidelity of canonical non-homologous end joining (C-NHEJ), we developed an assay to detect EJ between distal ends of two Cas9-induced chromosomal breaks that are joined without causing insertion/deletion mutations (indels). Here we find that such EJ requires several core C-NHEJ factors, including XLF. Using variants of this assay, we find that C-NHEJ is required for EJ events that use 1–2, but not ≥3, nucleotides of terminal microhomology. We also investigated XLF residues required for EJ without indels, finding that one of two binding domains is essential (L115 or C-terminal lysines that bind XRCC4 and KU/DNA, respectively), and that disruption of one of these domains sensitizes XLF to mutations that affect its dimer interface, which we examined with molecular dynamic simulations. Thus, C-NHEJ, including synergistic function of distinct XLF domains, is required for EJ of chromosomal breaks without indels.

Date: 2018
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DOI: 10.1038/s41467-018-04867-5

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