The non-homologous end-joining factor Nej1 inhibits resection mediated by Dna2-Sgs1 at DNA double strand breaks [Molecular Bases of Disease]

Double strand breaks (DSBs) represent highly deleterious DNA damage and need to be accurately repaired. Homology directed repair (HDR) and non-homologous end-joining (NHEJ) are the two major DSB repair pathways that are highly conserved from yeast to mammals. The choice between these pathways is largely based on 5′ to 3′ DNA resection, and NHEJ proceeds only if resection has not initiated. In yeast, yKu70/80 (Ku) rapidly localizes to the break, protecting DNA ends from nuclease accessibility and recruits additional NHEJ factors, including Nej1 and Lif1. Cells harboring the nej1-V338A mutant exhibit NHEJ-mediated repair deficiencies and hyper-resection 0.15 kb from the DSB that was dependent on the nuclease activity of Dna2-Sgs1. The integrity of Nej1 is also important for inhibiting long-range resection, 4.8 kb from the break, and for preventing the formation of large genomic deletions at sizes > 700 bp around the break. Nej1V338A localized to an HO-induced DSB similarly to WT Nej1 indicating that the Nej1-Lif1 interaction becomes mainly critical for blocking hyper-resection after their recruitment to the DSB. This work highlights that Nej1 inhibits 5′ DNA hyper-resection mediated by Dna2-Sgs1, a function distinct from its previously reported role in supporting Dnl4 ligase activity and has implications for repair pathway choice and resection regulation upon DSB formation.

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