Coupling DNA Damage and Repair: an Essential Safeguard during Programmed DNA Double-Strand Breaks?

Bétermier, Mireille; Borde, Valérie; Villartay, Jean‐Pierre de

doi:10.1016/j.tcb.2019.11.005

Cited by 23 publications

(20 citation statements)

References 89 publications

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“…We previously proposed a model of "double DNA repair synapse" during V(D)J recombination according to which the X4-Xlf "filament" and the RAG1/2 post cleavage complex (PCC), together with ATM and PAXX, provide two complementary means of DNA end synapsis (Abramowski et al, 2018;Betermier et al, 2020;Lescale, Abramowski, et al, 2016). To address the role of X4 in this model, we crossed Xrcc4 M61R onto Paxx-/-and Atm-/-mice (hereafter denoted Xrcc4 M61R -Paxx and Xrcc4 M61R -Atm).…”

Section: Paxx and Atm Are Compensatory Factors For X4 In Lymphoid Developmentmentioning

confidence: 99%

“…Living organisms face DNA double-strand breaks (DSBs), the most toxic DNA lesions, from random or programmed (prDSBs) origins (Betermier, Borde, & de Villartay, 2020), such as during the development of the adaptive immune system through V(D)J recombination. V(D)J recombination results in the somatic rearrangement of variable (V), diversity (D), and joining (J) elements of antigen receptor loci in T-and B-cell precursors (Jung, Giallourakis, Mostoslavsky, & Alt, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…To acount for this, functional redundancy, we proposed a model in which prDSBs may benefit from evolutionary conserved DNA repair mechanisms as to avoid their intrinsic oncogenic potential (Betermier et al, 2020). In the particular context of V(D)J recombination, this mechanism would operate through a redundant "double DNA repair synapse", which strictly operates during V(D)J recombination to prevent genomic instability, but not in case of genotoxic-induced DNA damage (Abramowski et al, 2018;Lescale, Abramowski, et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development

Roch

Abramowski

Étienne

et al. 2021

eLife

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We developed a Xrcc4M61R separation of function mouse line to overcome the embryonic lethality of Xrcc4 deficient mice. XRCC4M61R protein does not interact with Xlf, thus obliterating XRCC4-Xlf filament formation while preserving the ability to stabilize DNA Ligase IV. X4M61R mice, which are DNA repair deficient, phenocopy the Nhej1-/- (known as Xlf -/-) setting with a minor impact on the development of the adaptive immune system. The core NHEJ DNA repair factor XRCC4 is therefore not mandatory for V(D)J recombination aside from its role in stabilizing DNA ligase IV. In contrast, Xrcc4M61R mice crossed on Paxx-/-, Nhej1-/-, or Atm-/- backgrounds are severely immunocompromised, owing to aborted V(D)J recombination as in Xlf-Paxx and Xlf-Atm double KO settings. Furthermore, massive apoptosis of post-mitotic neurons causes embryonic lethality of Xrcc4M61R -Nhej1-/- double mutants. These in vivo results reveal new functional interplays between XRCC4 and PAXX, ATM and Xlf in mouse development and provide new insights in the understanding of the clinical manifestations of human XRCC4 deficient condition, in particular its absence of immune deficiency.

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Section: Paxx and Atm Are Compensatory Factors For X4 In Lymphoid Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development

Roch

Abramowski

Étienne

et al. 2021

eLife

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“…We speculate that functional diversification of duplicated KU genes in ciliates and the pressure for precise IES excision may have favored the emergence of different types of coupling between DNA double-strand endonucleases and DSB repair factors, as a solution to face the threat represented by massive programmed rearrangements on genome integrity. Thus, work on ciliates may provide a general framework for the coupling between DNA cleavage and DSB repair during other programmed biological processes, such as V(D)J recombination of immunoglobulin genes in vertebrates or meiosis (discussed in [49]).…”

Section: Plos Geneticsmentioning

confidence: 99%

Functional diversification of Paramecium Ku80 paralogs safeguards genome integrity during precise programmed DNA elimination

et al. 2020

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Gene duplication and diversification drive the emergence of novel functions during evolution. Because of whole genome duplications, ciliates from the Paramecium aurelia group constitute a remarkable system to study the evolutionary fate of duplicated genes. Paramecium species harbor two types of nuclei: a germline micronucleus (MIC) and a somatic macronucleus (MAC) that forms from the MIC at each sexual cycle. During MAC development, 45,000 germline Internal Eliminated Sequences (IES) are excised precisely from the genome through a 'cut-and-close' mechanism. Here, we have studied the P. tetraurelia paralogs of KU80, which encode a key DNA double-strand break repair factor involved in non-homologous end joining. The three KU80 genes have different transcription patterns, KU80a and KU80b being constitutively expressed, while KU80c is specifically induced during MAC development. Immunofluorescence microscopy and high-throughput DNA sequencing revealed that Ku80c stably anchors the PiggyMac (Pgm) endonuclease in the developing MAC and is essential for IES excision genome-wide, providing a molecular explanation for the previously reported Ku-dependent licensing of DNA cleavage at IES ends. Expressing Ku80a under KU80c transcription signals failed to complement a depletion of endogenous Ku80c, indicating that the two paralogous proteins have distinct properties. Domain-swap experiments identified the α/β domain of Ku80c as the major determinant for its specialized function, while its C-terminal part is required for excision of only a small subset of IESs located in IES-dense regions. We conclude that Ku80c has acquired the ability to license Pgm-dependent DNA cleavage, securing precise DNA elimination during programmed rearrangements. The present study thus provides novel evidence for functional diversification of genes issued from a whole-genome duplication.

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“…All living organisms have to face DNA damage, and particularly DNA double-strand breaks (DSBs), 3 which are considered the most toxic DNA lesions for cells and have either exogenous or endogenous origins (1). Development of the adaptive immune system early in life is a major source of programmed DSBs (prDSB), which are introduced by recombination-acti-vating genes 1 and 2 (RAG1/2) during somatic DNA rearrangement (V(D)J recombination) of variable (V), diversity (D), and joining (J) elements of the T cell receptor and immunoglobulin genes in T and B cells in the thymus and bone marrow (BM), respectively (2,3).…”

mentioning

confidence: 99%

An in vivo study of the impact of deficiency in the DNA repair proteins PAXX and XLF on development and maturation of the hemolymphoid system

Musilli¹,

Abramowski

Roch

et al. 2020

Journal of Biological Chemistry

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Repair of DNA double-strand breaks by the nonhomologous end joining pathway is central for proper development of the adaptive immune system. This repair pathway involves eight factors, including XRCC4-like factor (XLF)/Cernunnos and the paralog of XRCC4 and XLF, PAXX nonhomologous end joining factor (PAXX). Xlf−/− and Paxx−/− mice are viable and exhibit only a mild immunophenotype. However, mice lacking both PAXX and XLF are embryonic lethal because postmitotic neurons undergo massive apoptosis in embryos. To decipher the roles of PAXX and XLF in both variable, diversity, and joining recombination and immunoglobulin class switch recombination, here, using Cre/lox-specific deletion to prevent double-KO embryonic lethality, we developed two mouse models of a conditional Xlf KO in a Paxx−/− background. Cre expressed under control of the iVav or CD21 promoter enabled Xlf deletion in early hematopoietic progenitors and splenic mature B cells, respectively. We demonstrate the XLF and PAXX interplay during variable, diversity, and joining recombination in vivo but not during class switch recombination, for which PAXX appeared to be fully dispensable. Xlf/Paxx double KO in hematopoietic progenitors resulted in a shorter lifespan associated with onset of thymic lymphomas, revealing a genome caretaking function of XLF/PAXX.

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Coupling DNA Damage and Repair: an Essential Safeguard during Programmed DNA Double-Strand Breaks?

Cited by 23 publications

References 89 publications

An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development

An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development

Functional diversification of Paramecium Ku80 paralogs safeguards genome integrity during precise programmed DNA elimination

An in vivo study of the impact of deficiency in the DNA repair proteins PAXX and XLF on development and maturation of the hemolymphoid system

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