scholarly journals Deletion of Ku70, Ku80, or Both Causes Early Aging without Substantially Increased Cancer

2007 ◽  
Vol 27 (23) ◽  
pp. 8205-8214 ◽  
Author(s):  
Han Li ◽  
Hannes Vogel ◽  
Valerie B. Holcomb ◽  
Yansong Gu ◽  
Paul Hasty
Keyword(s):  
Genetic Background ◽  
Double Mutant ◽  
Severe Combined Immunodeficiency ◽  
Nonhomologous End Joining ◽  
Mutant Mice ◽  
Combined Immunodeficiency ◽  
End Joining ◽  
High Incidence ◽  
Early Aging ◽  
Increased Sensitivity

ABSTRACT Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in the reported phenotypes. For example, only Ku70 mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80 mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 functions outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds or environments influence the phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70, Ku80, and double-mutant mice in the same genetic background raised in the same environment. We show that these three cohorts have similar phenotypes that most resemble the previous report for Ku80 mutant mice, i.e., early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.

scholarly journals Gene Targeting in Aspergillus fumigatus by Homologous Recombination Is Facilitated in a Nonhomologous End- Joining-Deficient Genetic Background

2006 ◽  
Vol 5 (1) ◽  
pp. 212-215 ◽  
Author(s):  
Sven Krappmann ◽  
Christoph Sasse ◽  
Gerhard H. Braus
Keyword(s):  
Homologous Recombination ◽  
Aspergillus Fumigatus ◽  
Gene Targeting ◽  
Mutant Strain ◽  
Genetic Background ◽  
Opportunistic Pathogen ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Gene Encoding

ABSTRACT The akuA gene encoding the Ku70 component of the nonhomologous end-joining machinery was deleted in the opportunistic pathogen Aspergillus fumigatus. No obvious phenotype could be assessed for the corresponding mutant strain but relative frequencies of homologous recombination were increased as deduced from targeting the laccase-encoding abr2 gene.

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

2020 ◽  
Author(s):  
Sergio Castañeda-Zegarra ◽  
Qindong Zhang ◽  
Amin Alirezaylavasani ◽  
Marion Fernandez-Berrocal ◽  
Rouan Yao ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Embryonic Lethality ◽  
Combined Immunodeficiency ◽  
End Joining ◽  
Mild Phenotype ◽  
Reduced Body ◽  
Non Homologous End Joining ◽  
Mature Lymphocyte ◽  
And Function

AbstractNon-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, Ku70 and Ku80 form a heterodimer that recognizes DSBs and promotes recruitment and function of downstream factors PAXX, MRI, DNA-PKcs, Artemis, XLF, XRCC4, and LIG4. Mutations in several known NHEJ genes result in severe combined immunodeficiency (SCID). Inactivation of Mri, Paxx or Xlf in mice results in normal or mild phenotype, while combined inactivation of Xlf/Mri, Xlf/Paxx, or Xlf/Dna-pkcs leads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion of Trp53 rescues embryonic lethality in mice with combined deficiencies of Xlf and Mri. Furthermore, Xlf-/-Mri-/-Trp53+/- and Xlf-/-Paxx-/-Trp53+/- mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation of Mri/Paxx results in live-born mice with modest phenotype, and combined inactivation of Mri/Dna-pkcs results in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte development in vivo. Moreover, Mri genetically interacts with Dna-pkcs and Paxx.

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

Aging ◽  
2020 ◽  
Author(s):  
Sergio Castañeda-Zegarra ◽  
Qindong Zhang ◽  
Amin Alirezaylavasani ◽  
Marion Fernandez-Berrocal ◽  
Rouan Yao ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
End Joining ◽  
Non Homologous End Joining

scholarly journals Leaky Severe Combined Immunodeficiency in Mice Lacking Non-homologous End Joining Factors XLF and MRI

2020 ◽  
Author(s):  
Sergio Castaneda-Zegarra ◽  
Qindong Zhang ◽  
Amin Alirezaylavasani ◽  
Marion Fernandez-Berrocal ◽  
Rouan Yao ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Embryonic Lethality ◽  
Combined Immunodeficiency ◽  
End Joining ◽  
Mild Phenotype ◽  
Reduced Body ◽  
Non Homologous End Joining ◽  
Mature Lymphocyte ◽  
And Function

Non-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, Ku70 and Ku80 form a heterodimer that recognizes DSBs and promotes recruitment and function of downstream factors PAXX, MRI, DNA-PKcs, Artemis, XLF, XRCC4, and LIG4. Mutations in several known NHEJ genes result in severe combined immunodeficiency (SCID). Inactivation of Mri, Paxx or Xlf in mice results in normal or mild phenotype, while combined inactivation of Xlf/Mri, Xlf/Paxx, or Xlf/Dna-pkcs leads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion of Trp53 rescues embryonic lethality in mice with combined deficiencies of Xlf and Mri. Furthermore, Xlf-/-Mri-/-Trp53+/- and Xlf-/-Paxx-/-Trp53+/- mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation of Mri/Paxx results in live-born mice with modest phenotype, and combined inactivation of Mri/Dna-pkcs results in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte development in vivo. Moreover, Mri genetically interacts with Dna-pkcs and Paxx.

scholarly journals Treponema denticola in Disseminating Endodontic Infections

2006 ◽  
Vol 85 (8) ◽  
pp. 761-765 ◽  
Author(s):  
F. Foschi ◽  
J. Izard ◽  
H. Sasaki ◽  
V. Sambri ◽  
C. Prati ◽  
...  
Keyword(s):  
Dental Pulp ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Periodontal Pathogen ◽  
Treponema Denticola ◽  
Potential Importance ◽  
Combined Immunodeficiency ◽  
Wild Type ◽  
High Incidence ◽  
Endodontic Infections

Treponema denticola is a consensus periodontal pathogen that has recently been associated with endodontic pathology. In this study, the effect of mono-infection of the dental pulp with T. denticola and with polymicrobial "red-complex" organisms (RC) ( Porphyromonas gingivalis, Tannerella forsythia, and T. denticola) in inducing disseminating infections in wild-type (WT) and severe-combined-immunodeficiency (SCID) mice was analyzed. After 21 days, a high incidence (5/10) of orofacial abscesses was observed in SCID mice mono-infected with T. denticola, whereas abscesses were rare in SCID mice infected with the red-complex organisms or in wild-type mice. Splenomegaly was present in all groups, but only mono-infected SCID mice had weight loss. T. denticola DNA was detected in the spleen, heart, and brain of mono-infected SCID mice and in the spleen from mono-infected wild-type mice, which also had more periapical bone resorption. The results indicate that T. denticola has high pathogenicity, including dissemination to distant organs, further substantiating its potential importance in oral and linked systemic conditions.

scholarly journals A Human Severe Combined Immunodeficiency (SCID) Condition with Increased Sensitivity to Ionizing Radiations and Impaired V(D)J Rearrangements Defines a New DNA Recombination/Repair Deficiency

1998 ◽  
Vol 188 (4) ◽  
pp. 627-634 ◽  
Author(s):  
Nathalie Nicolas ◽  
Despina Moshous ◽  
Marina Cavazzana-Calvo ◽  
Dora Papadopoulo ◽  
Régina de Chasseval ◽  
...  
Keyword(s):  
Dna Repair ◽  
Ionizing Radiation ◽  
Chinese Hamster Ovary Cells ◽  
Severe Combined Immunodeficiency ◽  
Dna Recombination ◽  
Chinese Hamster ◽  
Combined Immunodeficiency ◽  
Recombination Repair ◽  
Increased Sensitivity ◽  
Rag 1

The products of recombination activating gene (RAG)1 and RAG2 initiate the lymphoid-specific phase of the V(D)J recombination by creating a DNA double-strand break (dsb), leaving hairpin-sealed coding ends. The next step uses the general DNA repair machinery of the cells to resolve this dsb. Several genes involved in both V(D)J recombination and DNA repair have been identified through the analysis of in vitro mutants (Chinese hamster ovary cells) and in vivo situations of murine and equine severe combined immunodeficiency (scid). These studies lead to the description of the Ku–DNA-dependent protein kinase complex and the XRCC4 factor. A human SCID condition is characterized by an absence of B and T lymphocytes. One subset of these patients also demonstrates an increased sensitivity to the ionizing radiation of their fibroblasts and bone marrow precursor cells. This phenotype is accompanied by a profound defect in V(D)J recombination with a lack of coding joint formation, whereas signal joints are normal. Functional and genetic analyses distinguish these patients from the other recombination/repair mutants, and thus define a new group of mutants whose affected gene(s) is involved in sensitivity to ionizing radiation and V(D)J recombination.

Immunologic Reconstitution in Severe Combined Immunodeficiency Following Transplantation With Parental Bone Marrow

PEDIATRICS ◽  
1976 ◽  
Vol 58 (3) ◽  
pp. 451-455
Author(s):  
Raif S. Geha ◽  
Artin Malakian ◽  
Gerard LeFranc ◽  
Denise Chayban ◽  
Jean-Louis Serre
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Immune Functions ◽  
Combined Immunodeficiency ◽  
Humoral Immune ◽  
Complete Restoration ◽  
The Family ◽  
High Incidence ◽  
Immunologic Reconstitution

A 9-month-old girl with severe combined immunodeficiency was transplanted with BM cells from her father. The child had complete restoration of cell-mediated immune functions. Humoral immune functions remain absent nine months after transplant. Child and father were HL-A identical and their lymphocytes were nonreactive in mixed lymphocyte culture. The parents of the child were first cousins and shared an HL-A haplotype. In countries like Lebanon, where there is a high incidence of first-cousin marriages (15%) and where villages are relatively isolated, the search for histocompatible graft donors should extend beyond the siblings to other members of the family.

scholarly journals A Unique Subset of Self-specific Intraintestinal T Cells Maintains Gut Integrity

2002 ◽  
Vol 195 (11) ◽  
pp. 1491-1497 ◽  
Author(s):  
Philippe Poussier ◽  
Terri Ning ◽  
Diponkar Banerjee ◽  
Michael Julius
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Intestinal Epithelium ◽  
Intestinal Inflammation ◽  
Severe Combined Immunodeficiency ◽  
Mutant Mice ◽  
Combined Immunodeficiency ◽  
Β Cells ◽  
High Affinity ◽  
Chronic Intestinal Inflammation

Lymphocytes residing in the intestinal epithelium are exclusively T cells and account for one of the largest collection of T cells in the organism. However, their function remains obscure. We and others have shown that the development of intestinal intraepithelial T cells is compromised in mutant mice prone to chronic intestinal inflammation. These results led us to directly assess their role in regulating the development of colitis secondary to transfer of primary splenic TCRαβ+CD4+CD45RBhi T cells into severe combined immunodeficiency (SCID) mice. Here we demonstrate that prior reconstitution of SCID recipients with intraintestinal TCRαβ+CD4−CD8α+β− T cells prevents disease, and does so in an interleukin (IL)-10–dependent fashion. In contrast, reconstitution with either TCRγδ+ or TCRαβ+CD4− CD8α+β+ intestinal T cells did not prevent colitis. TCRαβ+CD4−8α+β− T cells are unique to the intestinal epithelium of both rodents and humans. Previous repertoire analyses of TCRαβ+CD4−CD8α+β− T cells revealed a high proportion of cells expressing high affinity, self-specific TCR within this subset. We demonstrate that monoclonal, self specific TCRαβ+CD4−CD8α+β− cells derived from TCR transgenic mice also prevent the onset of colitis. Thus, intestinal TCRαβ+CD4−CD8α+β− T cells, selected based on their self-reactivity, maintain gut integrity in a IL-10–dependent fashion.

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