Journal
SCIENCE
Volume 347, Issue 6218, Pages 185-188Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1261971
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Funding
- Wellcome Trust [WT 093165, WT092096]
- Cancer Research UK (CRUK) program [C6/A11224]
- European Research Council
- European Community Seventh Framework Programme [HEALTH-F2-2010-259893]
- CRUK [06946/A1442]
- CRUK Career Development Fellowship [C28598/A9787]
- Cancer Research UK [11224, 18796, 9787] Funding Source: researchfish
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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 Ku-dependent DNA ligation in vitro and assembly of core nonhomologous end-joining (NHEJ) factors on damaged chromatin in cells. These findings identify PAXX as a new component of the NHEJ machinery.
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