Journal
EMBO JOURNAL
Volume 32, Issue 1, Pages 112-125Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2012.304
Keywords
DNA repair; DNA strand break; end joining
Categories
Funding
- MRC
- CR-UK
- BBSRC [BB/F013930/1] Funding Source: UKRI
- MRC [MR/J006750/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F013930/1] Funding Source: researchfish
- Cancer Research UK [13078, 14532] Funding Source: researchfish
- Medical Research Council [MR/J006750/1, G0801130B] Funding Source: researchfish
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Non-homologous end joining (NHEJ) is critical for the maintenance of genetic integrity and DNA double-strand break (DSB) repair. NHEJ is regulated by a series of interactions between core components of the pathway, including Ku heterodimer, XLF/Cemunnos, and XRCC4/DNA Ligase 4 (Lig4). However, the mechanisms by which these proteins assemble into functional protein-DNA complexes are not fully understood. Here, we show that the von Willebrand (vWA) domain of Ku80 fulfills a critical role in this process by recruiting Aprataxin-and-PNK-Like Factor (APLF) into Ku-DNA complexes. APLF, in turn, functions as a scaffold protein and promotes the recruitment and/or retention of XRCC4-Lig4 and XLF, thereby assembling multi-protein Ku complexes capable of efficient DNA ligation in vitro and in cells. Disruption of the interactions between APLF and either Ku80 or XRCC4-Lig4 disrupts the assembly and activity of Ku complexes, and confers cellular hypersensitivity and reduced rates of chromosomal DSB repair in avian and human cells, respectively. Collectively, these data identify a role for the vWA domain of Ku80 and a molecular mechanism by which DNA ligase proficient complexes are assembled during NHEJ in mammalian cells, and reveal APLF to be a structural component of this critical DSB repair pathway. The EMBO Journal (2013) 32, 112-125. doi: 10.1038/emboj.2012.304; Published online 23 November 2012
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