Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI

Castañeda‐Zegarra, Sergio; Zhang, Qindong; Alirezaylavasani, Amin; Oksenych, Valentyn

doi:10.1101/2020.03.04.976829

Cited by 7 publications

(32 citation statements)

References 42 publications

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“…Dna‐pkcs −/− Paxx −/− mice are live‐born, fertile and indistinguishable from Dna‐pkcs −/− littermates 39 . Furthermore, Mri −/− Paxx −/− mice possess nearly no detectable phenotype, similar to single‐deficient Mri −/− and Paxx −/− mice 42 . In contrast, Dna‐pkcs −/− Mri −/− mice are embryonic lethal 42 .…”

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 97%

“…Thus, there is evidence that Xlf genetically interacts with Dna‐pkcs , 38‐40 Paxx 18,19,36,39,42 and Mri 23,42 . Further transgenic mouse studies address whether Dna‐pkcs genetically interacts with Paxx and Mri , and whether Paxx genetically interacts with Mri.…”

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

“…Mice lacking both XLF and PAXX possess late embryonic lethality, increased genomic instability and immunodeficiency; and Xlf −/− Paxx −/− lymphocytes are unable to sustain repair of both SEs and CEs generated during V(D)J recombination 18,19,36,41 . The embryonic lethality of Xlf −/− Paxx −/− mice is p53‐dependent, and both Xlf −/− Paxx −/− Trp53 +/− and Xlf −/− Paxx −/− Trp53 −/− mice are live‐born, but possess significant weight reduction and a leaky SCID phenotype with nearly no mature B and T lymphocytes 39,42 …”

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

“…Furthermore, Xlf −/− Mri −/− double knockout mice are embryonic lethal, 23 but can be rescued by inactivation of one or two alleles of Trp53 42 . Mice lacking both XLF and MRI are characterized by leaky SCID with nearly no mature B and T lymphocytes due to the V(D)J recombination defect 23 .…”

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

“…In particular, the lymphocytes lacking both XLF and MRI are unable to efficiently ligate both RAG‐mediated SEs and CEs in vitro 23 . Both the double‐deficient mouse model lacking XLF and PAXX and the model lacking XLF and MRI are characterized by leaky SCID with low but detectable levels of mature B and T lymphocytes 42 . This phenotype is likely possible due to residual NHEJ activity in developing Xlf −/− Paxx −/− and Xlf −/− Mri −/− lymphocytes in vivo 39,42 …”

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

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Genetic interaction between the non‐homologous end‐joining factors during B and T lymphocyte development: In vivo mouse models

et al. 2020

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DNA double-strand breaks (DSBs) are generated both extrinsically, for example, by chemotherapeutic agents, and physiologically, for example, during V(D)J recombination in developing B and T lymphocytes, and class switch recombination (CSR) in activated mature B cells. 1,2 The DNA damage response (DDR) pathway is initiated upon the induction of DSBs. Ataxia telangiectasia mutated (ATM) is a DDR regulator protein kinase that phosphorylates

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Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 97%

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

Section: Non‐homologous End‐joining–deficient Micementioning

confidence: 99%

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Genetic interaction between the non‐homologous end‐joining factors during B and T lymphocyte development: In vivo mouse models

et al. 2020

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Acetyltransferases GCN5 and PCAF are required for B lymphocyte maturation in mice

Oksenych

2021

Preprint

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B lymphocyte development includes two DNA recombination processes, the V(D)J recombina-tion of immunoglobulin (Igh) gene variable region and class switching when the Igh constant regions are changed from IgM to IgG, IgA, or IgE. The V(D)J recombination is required for suc-cessful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. The CSR occurs outside the bone marrow when mature B cells migrate to periph-eral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR de-pend on an open chromatin state that makes DNA accessible to specific enzymes, recombina-tion activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated by complex breeding a mouse model with B cells lacking both GCN5 and PCAF. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B cell development in vivo.

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CIRKIL Exacerbates Cardiac Ischemia/Reperfusion Injury by Interacting With Ku70

Hongwen

Zhang

et al. 2022

Circulation Research

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Background: Ku70 participates in several pathological processes through mediating repair of DNA double-strand breaks. Our previous study has identified a highly conserved long noncoding RNA cardiac ischemia reperfusion associated Ku70 interacting lncRNA (CIRKIL) that was upregulated in myocardial infarction. The study aims to investigate whether CIRKIL regulates myocardial ischemia/reperfusion (I/R) through binding to Ku70. Methods: CIRKIL transgenic and knockout mice were subjected to 45-minute ischemia and 24-hour reperfusion to establish myocardial I/R model. RNA pull-down and RNA immunoprecipitation assay were used to detect the interaction between CIRKIL and Ku70. Results: The expression of CIRKIL was increased in I/R myocardium and H 2 O 2 -treated cardiomyocytes. Overexpression of CIRKIL increased the expression of γH 2 A.X, a specific marker of DNA double-strand breaks and aggravated cardiomyocyte apoptosis, whereas knockdown of CIRKIL produced the opposite changes. Transgenic overexpression of CIRKIL aggravated cardiac dysfunction, enlarged infarct area, and worsened cardiomyocyte damage in I/R mice. Knockout of CIRKIL alleviated myocardial I/R injury. Mechanistically, CIRKIL directly bound to Ku70 to subsequently decrease nuclear translocation of Ku70 and impair DNA double-strand breaks repair. Concurrent overexpression of Ku70 mitigated CIRKIL overexpression-induced myocardial I/R injury. Furthermore, knockdown of human CIRKIL significantly suppressed cell damage induced by H 2 O 2 in adult human ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes. Conclusions: CIRKIL is a detrimental factor in I/R injury acting via regulating nuclear translocation of Ku70 and DNA double-strand breaks repair. Thus, CIRKIL might be considered as a novel molecular target for the treatment of cardiac conditions associated with I/R injury.

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Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI

Cited by 7 publications

References 42 publications

Genetic interaction between the non‐homologous end‐joining factors during B and T lymphocyte development: In vivo mouse models

Genetic interaction between the non‐homologous end‐joining factors during B and T lymphocyte development: In vivo mouse models

Acetyltransferases GCN5 and PCAF are required for B lymphocyte maturation in mice

CIRKIL Exacerbates Cardiac Ischemia/Reperfusion Injury by Interacting With Ku70

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