DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair

  • Science. 2015 Jan 9;347(6218):185-188. doi: 10.1126/science.1261971.
Takashi Ochi  #  1 ,  Andrew N Blackford  #  2 ,  Julia Coates  2 ,  Satpal Jhujh  2 ,  Shahid Mehmood  3 ,  Naoka Tamura  4 ,  Jon Travers  2 ,  Qian Wu  1 ,  Viji M Draviam  4 ,  Carol V Robinson  3 ,  Tom L Blundell  1 ,  Stephen P Jackson  1  2  5
Affiliations
  • 1. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
  • 2. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
  • 3. Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK.
  • 4. Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
  • 5. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • # Contributed equally.
PMID: 25574025 DOI: 10.1126/science.1261971
Abstract

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.