The scid mutation in mice causes a general defect in DNA repair

Fulop, G. M.; Phillips, Robert A.

doi:10.1038/347479a0

Cited by 490 publications

(230 citation statements)

References 17 publications

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“…The appearance of polyploid cells in the testes of p53-null mice may be similarly related to the normal role of p53 in the surveillance of recombination intermediates in spermatocytes and the elimination of cells that undergo abnormal recombination (Rotter et al, 1993). Our observation that the level of p53 protein is similar in BALB/c and FI (scid/+) thymocytes and is lower than that found in scid thymocytes supports the surveillance model of p53 function since the F1 cells are believed to be phenotypically normal (Fulop and Phillips, 1990). We note, however, that this e ect of DNA-PK CS is not restricted to p53 protein levels; the level of b-tubulin but not GSK-3b, was also elevated in the Ova-scid cells compared with the BALB/c cells.…”

Section: Discussionsupporting

confidence: 56%

“…F1 cells were previously shown to have normal radiosensitivity and to undergo immunoglobulin gene rearrangement (Fulop and Phillips, 1990). Hence, the e ect of the scid mutation on radiation sensitivity and on gene rearrangement is recessive (Fulop and Phillips, 1990). We con®rmed that the radiation sensitivities of BALB/c and F1 thymocytes were indeed identical and di erent from that of Ova-scid thymocytes ( Figure 6) and that F1 but not scid thymocytes undergo normal rearrangement of the TCRd locus (data not shown).…”

Section: Resultsmentioning

confidence: 54%

“…We found comparable proportions of CD4 + CD8 + , CD4 7 CD8 7 , CD4 + and CD8 + thymocytes in BALB/c (80%, 5%, 13%, 2%), Ova-scid/+ (70%, 5%, 22%, 3%) and Ova-scid/scid (48%, 23%, 23%, 6%) mice. F1 cells were previously shown to have normal radiosensitivity and to undergo immunoglobulin gene rearrangement (Fulop and Phillips, 1990). Hence, the e ect of the scid mutation on radiation sensitivity and on gene rearrangement is recessive (Fulop and Phillips, 1990).…”

Section: Resultsmentioning

confidence: 99%

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Phosphorylation of p53 protein in response to ionizing radiation occurs at multiple sites in both normal and DNA-PK deficient cells

1999

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The tumour suppressor gene product, p53, is involved in mediating cellular responses to DNA damage including growth arrest and/or apoptosis. The mechanism by which p53 protein senses the presence of damaged DNA is not understood. The possibility that p53 may be posttranslationally modi®ed by enzymes that are activated in response to DNA damage including DNA-dependent protein kinase (DNA-PK), poly(ADP-ribose) polymerase and stress activated protein kinase has received considerable attention. Recent studies have indicated that DNA-PK is not required for the transactivation or apoptosis-promoting activities of p53 protein. However, the possibility that other functions of p53 may be dependent on phosphorylation by DNA-PK has not been explored. Here we describe a series of experiments that compares the expression, function and phosphorylation status of p53 protein in normal and DNA-PK-de®cient scid cells. While several novel p53 phosphoforms are generated in response to DNA damage in normal cells, the same phosphoforms are observed in scid cells.

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Section: Discussionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

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Phosphorylation of p53 protein in response to ionizing radiation occurs at multiple sites in both normal and DNA-PK deficient cells

1999

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“…20 In the NOD/SCID setting, deficiencies in DNA repair are driven by mutant catalytic subunit of DNA-dependent protein kinase (Prkdc), which is applicable to T and B lymphocytes with a propensity for lymphoma and thymoma. 21,22 By contrast, Prkdc mutation is of no consequence for liver cells. We confirmed this by normal liver test results and hepatic morphological features in healthy control NOD/ SCID mice, including absence of apoptosis or of increased Ki-67 expression.…”

Section: Discussionmentioning

confidence: 98%

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Bandi

Joseph

Berishvili

et al. 2011

The American Journal of Pathology

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Superior insights into molecular mechanisms of liver failure, which are not fully understood, will help strategies for inducing liver regeneration. We examined hepatotoxic mechanisms in mice homozygous for the severe combined immune deficiency mutation in the protein kinase, DNA-activated, catalytic polypeptide. Mice were treated with rifampicin, phenytoin, and monocrotaline. The ensuing acute liver failure was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with liver failure. We found extensive liver damage in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, inflammation, DNA damage-repair, and ataxia telangiectasia mutant (Atm) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with liver failure. Molecular abnormalities rapidly reversed, including in hepatic Atm and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that Atm signaling Drug-induced liver injury (DILI) often results in acute liver failure (ALF). 1 Acetaminophen (APAP) is the leading offender in causing ALF; however, despite extensive work, mechanisms of DILI by APAP are incompletely understood. [2][3][4][5] The identification of molecular pathways initiating or amplifying DILI will be highly significant for drug development and for preventing and/or treating ALF. After exposure to hepatotoxic drugs, perturbations in cell stress and toxicity pathways assume prominence. However, more information is required regarding intracellular signaling pathways that impart susceptibility to DILI. Similarly, more information is required regarding failure of liver regeneration in ALF. Nevertheless, establishing these mechanisms has been difficult in the available animal models of ALF. For instance, after exposure to toxic drugs or chemicals, some animals may exhibit rapid and irreversible mortality (eg, within 24 -30 hours after APAP), whereas other animals may recover spontaneously.

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“…The XRCC4/ Cernunnos/DNA-LigaseIV complex finally seals coding and signal joins. NHEJ, non-homologous end-joining; IgH, immunoglobulin H general DNA repair defect accompanied by an increased sensitivity to IR or other agents causing DNA dsb, provided the initial link between V(D)J recombination and general DNA dsb repair (Fulop and Phillips, 1990;Biedermann et al, 1991;Hendrickson et al, 1991). The faulty V(D)J recombination in scid mice can be demonstrated in pre-T and pre-B cells using extrachromosomal V(D)J recombination substrates (Lieber et al, 1988) as well as on endogenous T-cell receptor loci in ex vivo isolated thymocytes (Roth et al, 1992).…”

Section: V(d)j Recombination Deficiencies In Humans: Rs-scids and Scimentioning

confidence: 99%

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

et al. 2007

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The immune system is the site of intense DNA damage/ modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the nonhomologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways. Oncogene (2007) 26, 7780-7791; doi:10.1038/sj.onc.1210875 Keywords: V(D)J recombination; class switch recombination; SCID; Artemis; Cernunnos; NHEJ V(D)J recombination and CSR: two rearrangement processes that shape the immune system repertoire B and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the B-cell receptor and T-cell receptor, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Figure 1) which assembles previously scattered Variable (V), Diversity (D) and Joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism (Tonegawa, 1983). The reaction is initiated by the lymphoid-specific factors, Rag1 and Rag2, which recognize recombination signal sequences (RSS) that flank all V, D and J gene units and introduce a DNA dsb at the border of the RSS (see Dudley et al. (2005) for a review on V(D)J recombination). The resulting DNA double-strand break (DNA dsb) is resolved by the ubiquitous DNA repair machinery known as non-homologous end-joining (NHEJ). The convergent efforts of scientists in the immunology and DNA repair fields were decisive in defining the various actors and molecular mechanisms of this DNA repair pathway over the years as will be discussed below.The terminal maturation of B lymphocytes, which occurs in germinal centres of secondary lymphoid organs upon antigen recognition, is accompanied by two additional molecular processing of immunoglobulin genes that increase the efficiency of the humoral response: (1) the class switch recombination (CSR, Figure 2) exchanges the immunoglobulin (Ig) constant region (CH), thus modifying the function of the Ig without altering its antigenic specificity (Manis et al., 2002b) and (2) somatic hypermutations are introduced in the Ig variable domains, thus increasing their affinity for antigen (Papavasiliou and Schatz, 2002). These two events ar...

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The scid mutation in mice causes a general defect in DNA repair

Cited by 490 publications

References 17 publications

Phosphorylation of p53 protein in response to ionizing radiation occurs at multiple sites in both normal and DNA-PK deficient cells

Phosphorylation of p53 protein in response to ionizing radiation occurs at multiple sites in both normal and DNA-PK deficient cells

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

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