期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 25, 期 10, 页码 971-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0133-6
关键词
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资金
- ARC program [SLS220120605310]
- ANR [ANR-12-SVSE8-012, CE12 2017 NHEJLIG4]
- INCA DomRep [PLBIO 2012-280]
- CEFIPRA grant [5203C]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INBS-05]
- National Institutes of Health [CA187612, GM108119]
- American Cancer Society [RSG DMC-16-241-01-DMC]
- Ligue Nationale Contre Le Cancer (Equipe labellisee)
- Electricite de France (EDF, Conseil de Radioprotection)
- Ligue Nationale Contre Le Cancer
- ITMO Cancer Aviesan (Alliance Nationale Pour les Sciences de la Vie et de la Sante, National Alliance for Life Science and Health) within the framework of Cancer Plan
- BBSRC [BB/L01386X/1] Funding Source: UKRI
The Ku70-Ku80 (Ku) heterodimer binds rapidly and tightly to the ends of DNA double-strand breaks and recruits factors of the non-homologous end-joining (NHEJ) repair pathway through molecular interactions that remain unclear. We have determined crystal structures of the Ku-binding motifs (KBM) of the NHEJ proteins APLF (A-KBM) and XLF (X-KBM) bound to a Ku-DNA complex. The two KBM motifs bind remote sites of the Ku80 alpha/beta domain. The X-KBM occupies an internal pocket formed by an unprecedented large outward rotation of the Ku80 alpha/beta domain. We observe independent recruitment of the APLF-interacting protein XRCC4 and of XLF to laser-irradiated sites via binding of A- and X-KBMs, respectively, to Ku80. Finally, we show that mutation of the X-KBM and A-KBM binding sites in Ku80 compromises both the efficiency and accuracy of end joining and cellular radiosensitivity. A- and X-KBMs may represent two initial anchor points to build the intricate interaction network required for NHEJ.
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