Multifunctional properties of Nej1 C-terminus promote end-joining and impact DNA double-strand break repair pathway choice.

DNA Repair (Amst)

Departments of Biochemistry & Molecular Biology and Oncology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine; University of Calgary, 3330 Hospital Drive N.W., Calgary AB T2N 4N1, Canada. Electronic address:

Published: July 2022

A DNA double strand break (DSB) is primarily repaired by one of two canonical pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). NHEJ requires no or minimal end processing for ligation, whereas HR requires 5' end resection followed by a search for homology. The main event that determines the mode of repair is the initiation of 5' resection because if resection starts, then NHEJ cannot occur. Nej1 is a canonical NHEJ factor that functions at the cross-roads of repair pathway choice and prior to its function in stimulating Dnl4 ligase. Nej1 competes with Dna2, inhibiting its recruitment to DSBs and thereby inhibiting resection. The highly conserved C-terminal region (CTR) of Nej1 (330-338) is important for two events that drive NHEJ as it stimulates ligation and inhibits resection, but it is dispensable for end-bridging. By combining nej1 point mutants with nuclease-dead dna2-1, we find that Nej1-F335 is essential for end-joining whereas V338 promotes NHEJ indirectly by inhibiting Dna2-mediated resection.

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Source
http://dx.doi.org/10.1016/j.dnarep.2022.103332DOI Listing

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