Synthetic lethality between PAXX and XLF in mammalian development

Balmus, Gabriel; Barros, Ana C.; Wijnhoven, Paul W.G.; Lescale, Chloé; Hasse, Hélène Lenden; Boroviak, Katharina; Sage, Carlos le; Doe, Brendan; Speak, Anneliese O.; Galli, Antonella; Jacobsen, Matt; Deriano, Ludovic; Adams, David J.; Blackford, Andrew N.; Jackson, Stephen

doi:10.1101/gad.290510.116

Cited by 76 publications

(167 citation statements)

References 29 publications

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“…Both XLF and PAXX share structural similarity with XRCC4 (62,64). Individual XLF and PAXX mutants display only a mild phenotype, but XLF PAXX double mutants are synthetically lethal in mice and reduce V(D)J recombination in human B lymphocytes (98)(99)(100)(101), suggesting that while they may be redundant, at least one is necessary for efficient repair by NHEJ. The main purpose of XLF and PAXX appears to be in providing additional structural support to stabilize two DNA ends, thereby enhancing the ability of XRCC4·Lig4.…”

Section: Xlf and Paxx Stimulate Ligation By The Xrcc4·lig4 Complexmentioning

confidence: 99%

Nonhomologous DNA end-joining for repair of DNA double-strand breaks

Pannunzio

Watanabe

Lieber

2018

Journal of Biological Chemistry

387

360

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Nonhomologous DNA end joining (NHEJ) is the predominant DSB repair pathway throughout the cell cycle and accounts for nearly all DSB repair outside of the S and G2 phases. NHEJ relies on Ku to thread onto DNA termini and thereby improve the affinity of the NHEJ enzymatic components consisting of polymerases (Pol m and Pol l), a nuclease (the Artemis·DNA-PKcs complex), and a ligase (XLF·XRCC4·Lig4 complex). Each of the enzymatic components is distinctive for its versatility in acting on diverse incompatible DNA end configurations coupled with a flexibility in loading order, resulting in many possible junctional outcomes from one DSB. DNA ends can either be directly ligated or, if the ends are incompatible, processed until a ligatable configuration is achieved that is often stabilized by up to 4 bp of terminal microhomology. Processing of DNA ends results in nucleotide loss or addition, explaining why DSBs repaired by NHEJ are rarely restored to their original DNA sequence. Thus, NHEJ is a single pathway with multiple enzymes at its disposal to repair DSBs, resulting in a diversity of repair outcomes.

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Section: Xlf and Paxx Stimulate Ligation By The Xrcc4·lig4 Complexmentioning

confidence: 99%

Nonhomologous DNA end-joining for repair of DNA double-strand breaks

Pannunzio

Watanabe

Lieber

2018

Journal of Biological Chemistry

387

360

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“…[8][9][10][12][13][14][15] This suggested a possible functional complementation of PAXX deficiency in certain conditions.…”

mentioning

confidence: 99%

“…11 Surprisingly, for a NHEJ factor, the deficiency of PAXX does not systematically result in an increased sensitivity to ionizing radiation (IR) and the results of the various DNA repair assays are highly controversial, depending on the experimental settings. [8][9][10][12][13][14][15] This suggested a possible functional complementation of PAXX deficiency in certain conditions.…”

mentioning

confidence: 99%

PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice

et al. 2017

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The repair of DNA double-stranded breaks (DNAdsb) through non-homologous end joining (NHEJ) is a prerequisite for the proper development of the central nervous system and the adaptive immune system. Yet, mice with Xlf or PAXX loss of function are viable and present with very mild immune phenotypes, although their lymphoid cells are sensitive to ionizing radiation attesting for the role of these factors in NHEJ. In contrast, we show here that mice defective for both Xlf and PAXX are embryonically lethal owing to a massive apoptosis of post-mitotic neurons, a situation reminiscent to XRCC4 or DNA Ligase IV KO conditions. The development of the adaptive immune system in Xlf − / − PAXX −/− E18.5 embryos is severely affected with the block of B-and T-cell maturation at the stage of IgH and TCRβ gene rearrangements, respectively. This damaging phenotype highlights the functional nexus between Xlf and PAXX, which is critical for the completion of NHEJ-dependent mechanisms during mouse development. Cell Death and Differentiation (2018) 25, 444-452; doi:10.1038/cdd.2017; published online 27 October 2017All living organisms are subjected to multitude sources of DNA damage during their lifespan, either as a result of external assault or endogenous physiological processes.1 Among endogenous sources of physiological DNAdsb is the somatic rearrangement of immunoglobulin (Ig) and TCR genes in B and T lymphocytes, respectively, during the diversification of the adaptive immune system through V(D)J recombination.2 DNA double-stranded breaks (DNAdsb) are considered the most toxic lesions. DNAdsbs are repaired by two main mechanisms: the homologous recombination (HR) in cycling cells, when a sister chromatid is available as DNA repair template, and the non-homologous end joining (NHEJ) during all phases of the cell cycle.NHEJ proceeds via the simple religation of DNA ends without the need for a repair template.3 Briefly, the NHEJ is composed of seven core factors comprising the Ku70/80/ DNA-PKcs (DNA-dependent protein kinase catalytic subunit) complex, which recognizes and protects the broken DNA ends, the Artemis endo/exonuclease, which participates, when needed, in processing the DNA ends and the XRCC4/ DNA-Ligase IV/Xlf complex, which ultimately reseals the DNA break. The critical function of the NHEJ apparatus in various aspects of higher eukaryote development has been extensively perceived in several animal and human pathological conditions. As emblematic examples, loss of function of either XRCC4 or DNA ligase IV results in embryonic lethality in mice 4,5 and mutations in Artemis or DNA-PKcs result in severe combined immunodeficiency conditions in both men and mice, owing to aborted V(D)J recombination. 6 In addition, defects in NHEJ results in genetic instability and the propensity to develop various types of cancers, notably leukemia and lymphomas. Recently, a new DNA repair factor, PAXX (PAralog of XRCC4 and Xlf, also known as C9orf142 or XLS), has been identified independently by three laboratories based on bioinformatic...

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“…Nous avons ainsi pu montrer que PAXX n'est pas nécessaire pour la réparation des DSB induites par RAG [14]. En accord avec ces résultats, les souris déficientes pour PAXX ont un système immunitaire normal [17]. Cependant, une double déficience de PAXX et XLF abolit la réparation des DSB générées par RAG, conduisant à un défaut sévère de la recombinaison V(D)J [14].…”

Section: Paxx Rejoint La Partieunclassified

“…veux central et un blocage complet du développement lymphocytaire [17]. De plus, les cellules déficientes PAXX/XLF sont extrêmement sensibles au stress génotoxique induisant des DSB [14].…”

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