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Interactome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway

Mengtan Xing,Mingrui Yang,W. Huo,F. Feng,Leizhen Wei,Wenxia Jiang,Shaokai Ning,Zhenxin Yan,Wen Li,Qingsong Wang,Mei Hou,Chunxia Dong,R. Guo,Ge Gao,J. Ji,S. Zha,Li Lan,Huanhuan Liang,Dongyi Xu

Published 2015 in Nature Communications

ABSTRACT

Non-homologous end joining (NHEJ) is a major pathway to repair DNA double-strand breaks (DSBs), which can display different types of broken ends. However, it is unclear how NHEJ factors organize to repair diverse types of DNA breaks. Here, through systematic analysis of the human NHEJ factor interactome, we identify PAXX as a direct interactor of Ku. The crystal structure of PAXX is similar to those of XRCC4 and XLF. Importantly, PAXX-deficient cells are sensitive to DSB-causing agents. Moreover, epistasis analysis demonstrates that PAXX functions together with XLF in response to ionizing radiation-induced complex DSBs, whereas they function redundantly in response to Topo2 inhibitor-induced simple DSBs. Consistently, PAXX and XLF coordinately promote the ligation of complex but not simple DNA ends in vitro. Altogether, our data identify PAXX as a new NHEJ factor and provide insight regarding the organization of NHEJ factors responding to diverse types of DSB ends. DNA double-strand breaks (DSBs), a highly deleterious form of DNA damage, are associated with multiple types of broken ends. Here, the authors identify a XRCC4-like factor that functions in the non-homologous end-joining DNA repair pathway to repair DSBs with complex broken ends.

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