PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair
Draviam Sastry, Viji
Robinson, Carol V
American Association for the Advancement of Science
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Ochi, T., Blackford, A., Coates, J., Jhujh, S., Mehmood, S., Tamura, N., Travers, J., et al. (2015). PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science, 347 (6218), 185-188. https://doi.org/10.1126/science.1261971
XRCC4 and XLF are two structurally-related proteins that function in DNA double-strand break (DSB) repair. Here, we identify human PAXX (PAralog of XRCC4 and XLF; also called C9orf142) as a new XRCC4-superfamily member, and show that its crystal structure resembles that of XRCC4. PAXX interacts directly with the DSB-repair protein Ku and is recruited to DNA-damage sites in cells. Using RNA interference and CRISPR-Cas9 to generate PAXX-/- cells, we demonstrate that PAXX functions with XRCC4 and XLF to mediate DSB repair and cell survival in response to DSB-inducing agents. Finally, we reveal that PAXX promotes Kudependent DNA ligation in vitro, and assembly of core non-homologous end-joining (NHEJ) factors on damaged chromatin in cells. These findings identify PAXX as a new component of the NHEJ machinery.
T.O. and T.L.B. are supported by the Wellcome Trust. The Jackson lab is funded by Cancer Research UK (CRUK) program grant C6/A11224, the European Research Council and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010- 259893 (DDResponse). Core infrastructure funding to the Jackson lab is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, supplemented by CRUK. V.M.D. is a CRUK Career Development Fellow. The Draviam lab is funded by a CRUK CDA (C28598/A9787).
Cancer Research UK (11224)
European Research Council (268536)
Wellcome Trust (092096/Z/10/Z)
Wellcome Trust (093167/Z/10/Z)
Cancer Research UK (A14492)
Cancer Research UK (A9787)
External DOI: https://doi.org/10.1126/science.1261971
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246822