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Article Dans Une Revue Science Advances Année : 2023

PAXX binding to the NHEJ machinery explains functional redundancy with XLF

Philippe Frit
Steven Hardwick
Taiana Maia de Oliviera

Résumé

Nonhomologous end joining is a critical mechanism that repairs DNA double-strand breaks in human cells. In this work, we address the structural and functional role of the accessory protein PAXX [paralog of x-ray repair cross-complementing protein 4 (XRCC4) and XRCC4-like factor (XLF)] in this mechanism. Here, we report high-resolution cryo–electron microscopy (cryo-EM) and x-ray crystallography structures of the PAXX C-terminal Ku-binding motif bound to Ku70/80 and cryo-EM structures of PAXX bound to two alternate DNA-dependent protein kinase (DNA-PK) end-bridging dimers, mediated by either Ku80 or XLF. We identify residues critical for the Ku70/PAXX interaction in vitro and in cells. We demonstrate that PAXX and XLF can bind simultaneously to the Ku heterodimer and act as structural bridges in alternate forms of DNA-PK dimers. Last, we show that engagement of both proteins provides a complementary advantage for DNA end synapsis and end joining in cells.
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Origine : Publication financée par une institution
Licence : CC BY - Paternité

Dates et versions

hal-04234621 , version 1 (10-10-2023)

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Murielle Seif-El-Dahan, Antonia Kefala-Stavridi, Philippe Frit, Steven Hardwick, Dima Chirgadze, et al.. PAXX binding to the NHEJ machinery explains functional redundancy with XLF. Science Advances , 2023, 9 (22), pp.eadg2834. ⟨10.1126/sciadv.adg2834⟩. ⟨hal-04234621⟩
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