APLF promotes the assembly and activity of non-homologous end joining protein complexes

Grundy, Gabrielle L, Rulten, Stuart L, Zeng, Zhihong, Arribas-Bosacoma, Raquel, Iles, Natasha, Manley, Katie, Oliver, Antony and Caldecott, Keith W (2013) APLF promotes the assembly and activity of non-homologous end joining protein complexes. The EMBO journal, 32 (1). pp. 112-125. ISSN 1460-2075

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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/Cernunnos, 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

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science
Depositing User: Antony Oliver
Date Deposited: 14 Feb 2013 14:40
Last Modified: 14 Feb 2013 14:40
URI: http://srodev.sussex.ac.uk/id/eprint/43765
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