PAXX Is an Accessory c-NHEJ Factor that Associates with Ku70 and Has Overlapping Functions with XLF

In mammalian cells, classical non-homologous end joining (c-NHEJ) is critical for DNA double-strand break repair induced by ionizing radiation and during V(D)J recombination in developing B and T lymphocytes. Recently, PAXX was identified as a c-NHEJ core component. We report here that PAXX-deficien...

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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 17; no. 2; pp. 541 - 555
Main Authors: Tadi, Satish K., Tellier-Lebègue, Carine, Nemoz, Clément, Drevet, Pascal, Audebert, Stéphane, Roy, Sunetra, Meek, Katheryn, Charbonnier, Jean-Baptiste, Modesti, Mauro
Format: Journal Article
Language:English
Published: United States Elsevier Inc 04.10.2016
Elsevier
Subjects:
B-Lymphocytes - metabolism
DNA Breaks, Double-Stranded
DNA double-strand break repair
DNA End-Joining Repair - genetics
DNA ligase 4
DNA Repair - genetics
DNA Repair Enzymes - genetics
DNA Repair Enzymes - metabolism
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
HCT116 Cells
Humans
Ku Autoantigen - chemistry
Ku Autoantigen - genetics
Ku Autoantigen - metabolism
Ku70
Life Sciences
MMEJ
NHEJ
PAXX
T-Lymphocytes - metabolism
V(D)J recombination
V(D)J Recombination - genetics
XLF
XRCC4
Ku70
DNA double-strand break repair
MMEJ
XLF
PAXX
XRCC4
V(D)J recombination
DNA ligase 4
Ku
NHEJ
ISSN:2211-1247, 2211-1247
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Summary:In mammalian cells, classical non-homologous end joining (c-NHEJ) is critical for DNA double-strand break repair induced by ionizing radiation and during V(D)J recombination in developing B and T lymphocytes. Recently, PAXX was identified as a c-NHEJ core component. We report here that PAXX-deficient cells exhibit a cellular phenotype uncharacteristic of a deficiency in c-NHEJ core components. PAXX-deficient cells display normal sensitivity to radiomimetic drugs, are proficient in transient V(D)J recombination assays, and do not shift toward higher micro-homology usage in plasmid repair assays. Although PAXX-deficient cells lack c-NHEJ phenotypes, PAXX forms a stable ternary complex with Ku bound to DNA. Formation of this complex involves an interaction with Ku70 and requires a bare DNA extension for stability. Moreover, the relatively weak Ku-dependent stimulation of LIG4/XRCC4 activity by PAXX is unmasked by XLF ablation. Thus, PAXX plays an accessory role during c-NHEJ that is largely overlapped by XLF’s function. [Display omitted] •PAXX interaction with Ku threaded onto DNA requires a bare DNA extension•PAXX interacts with the Ku70 subunit•PAXX is dispensable for V(D)J recombination and has no core c-NHEJ phenotype•PAXX’s function in c-NHEJ is masked by XLF Tadi et al. find that PAXX interacts with Ku threaded on DNA via the Ku70 subunit and requires a bare DNA extension for stability. They show that PAXX’s function overlaps with c-NHEJ factor XLF, explaining why its ablation has only a mild effect on NHEJ.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2016.09.026