Journal
DNA REPAIR
Volume 115, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.dnarep.2022.103332
Keywords
DSB repair; Non-homologous end-joining (NHEJ); 5? resection; Repair pathway choice; Nej1; Dna2
Categories
Funding
- CIHR [MOP-82736, MOP-137062]
- NSERC [418122]
- Cumming School of Medicine at University of Calgary
- Western Economic Diversification (WED)
- Alberta Economic Development and Trade (AEDT) , Canada
- International Microbiome Centre
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A DNA double strand break can be repaired by either non-homologous end-joining (NHEJ) or homologous recombination (HR). Nej1 is a key factor in NHEJ that inhibits resection and stimulates ligation. The C-terminal region of Nej1 plays a vital role in promoting NHEJ.
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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