Sequential division of labor between PAXX and XLF drives NHEJ synaptic complex stability and maturation
Abstract
DNA double-strand breaks (DSBs) are primarily repaired by non-homologous end joining (NHEJ), which tethers and ligates DNA ends within a synaptic complex. PAXX is an NHEJ accessory factor related to XRCC4 and XLF, but its mechanistic role and genetic interaction with XLF are unclear. Using biochemical assays and single-molecule imaging within Xenopus laevis egg extracts and human cell assays, we show that PAXX bridges DNA ends by using its disordered tails to bind opposing Ku molecules. This PAXX tether substantially extends long-range synaptic complex (LRSC) lifetime and modestly stabilizes the short-range synaptic complex (SRSC). LRSC stabilization increases XLF residence and promotes the LRSC-to-SRSC transition. Using domain-swapped chimeras, we demonstrate that PAXX’s tails provide synaptic stabilization, whereas XLF’s heads interact with XRCC4 to drive the LRSC-to-SRSC transition: an XLF head-PAXX tail chimera recapitulates the functions of both proteins, revealing complementary, sequential roles for PAXX and XLF in NHEJ.
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BibTeX
@misc{zhang2026sequential,
title = {{Sequential division of labor between PAXX and XLF drives NHEJ synaptic complex stability and maturation}},
author = {Jinghang Zhang and Philippe Frit and Andrew T Moreno and Nadia Barboule and Patrick Calsou and Sébastien Britton and Joseph J Loparo},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.64898/2026.08.10.743781},
url = {https://hal.science/hal-05787444v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Sequential division of labor between PAXX and XLF drives NHEJ synaptic complex stability and maturation
AU - Jinghang Zhang
AU - Philippe Frit
AU - Andrew T Moreno
AU - Nadia Barboule
AU - Patrick Calsou
AU - Sébastien Britton
AU - Joseph J Loparo
PY - 2026
DA - 2026/08/12
PB - HAL
DO - 10.64898/2026.08.10.743781
UR - https://hal.science/hal-05787444v1
AB - DNA double-strand breaks (DSBs) are primarily repaired by non-homologous end joining (NHEJ), which tethers and ligates DNA ends within a synaptic complex. PAXX is an NHEJ accessory factor related to XRCC4 and XLF, but its mechanistic role and genetic interaction with XLF are unclear. Using biochemical assays and single-molecule imaging within Xenopus laevis egg extracts and human cell assays, we show that PAXX bridges DNA ends by using its disordered tails to bind opposing Ku molecules. This PAXX tether substantially extends long-range synaptic complex (LRSC) lifetime and modestly stabilizes the short-range synaptic complex (SRSC). LRSC stabilization increases XLF residence and promotes the LRSC-to-SRSC transition. Using domain-swapped chimeras, we demonstrate that PAXX’s tails provide synaptic stabilization, whereas XLF’s heads interact with XRCC4 to drive the LRSC-to-SRSC transition: an XLF head-PAXX tail chimera recapitulates the functions of both proteins, revealing complementary, sequential roles for PAXX and XLF in NHEJ.
ER -