Lescale Chloé, Lenden Hasse Hélène, Blackford Andrew N, Balmus Gabriel, Bianchi Joy J, Yu Wei, Bacoccina Léa, Jarade Angélique, Clouin Christophe, Sivapalan Rohan, Reina-San-Martin Bernardo, Jackson Stephen P, Deriano Ludovic
Departments of Immunology and Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Cell Rep. 2016 Sep 13;16(11):2967-2979. doi: 10.1016/j.celrep.2016.08.069. Epub 2016 Sep 2.
Paralog of XRCC4 and XLF (PAXX) is a member of the XRCC4 superfamily and plays a role in nonhomologous end-joining (NHEJ), a DNA repair pathway critical for lymphocyte antigen receptor gene assembly. Here, we find that the functions of PAXX and XLF in V(D)J recombination are masked by redundant joining activities. Thus, combined PAXX and XLF deficiency leads to an inability to join RAG-cleaved DNA ends. Additionally, we demonstrate that PAXX function in V(D)J recombination depends on its interaction with Ku. Importantly, we show that, unlike XLF, the role of PAXX during the repair of DNA breaks does not overlap with ATM and the RAG complex. Our findings illuminate the role of PAXX in V(D)J recombination and support a model in which PAXX and XLF function during NHEJ repair of DNA breaks, whereas XLF, the RAG complex, and the ATM-dependent DNA damage response promote end joining by stabilizing DNA ends.
XRCC4和XLF的旁系同源物（PAXX）是XRCC4超家族的成员，在非同源末端连接（NHEJ）中发挥作用，NHEJ是淋巴细胞抗原受体基因组装所必需的DNA修复途径。在此，我们发现PAXX和XLF在V(D)J重组中的功能被冗余的连接活性所掩盖。因此，PAXX和XLF联合缺陷导致无法连接RAG切割的DNA末端。此外，我们证明PAXX在V(D)J重组中的功能依赖于其与Ku的相互作用。重要的是，我们发现，与XLF不同，PAXX在DNA断裂修复过程中的作用不与ATM和RAG复合物重叠。我们的研究结果阐明了PAXX在V(D)J重组中的作用，并支持了一个模型，即PAXX和XLF在DNA断裂的NHEJ修复过程中发挥作用，而XLF、RAG复合物和ATM依赖性DNA损伤反应通过稳定DNA末端促进末端连接。
