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FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis.

ABSTRACT: Ataxia-telangiectasia mutated (ATM) kinase is a master regulator of the DNA damage response, and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. In this article, we show that in mouse models, knock-in ATM-R3057X mutation (Atm⁠ ^RX ⁠, corresponding to R3047X in human ATM) severely compromises ATM protein stability and causes T cell developmental defects, B cell Ig class-switch recombination defects, and infertility resembling ATM-null. The residual ATM-R3057X protein retains minimal yet functional measurable DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in Atm⁠ ^RX/RX ⁠ mice compared with Atm⁠ ^-/- ⁠. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that the presence of minimal residual ATM-R3057X protein can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.

SUBMITTER: Milanovic M

PROVIDER: S-EPMC9305077 | biostudies-literature |

REPOSITORIES: biostudies-literature

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FATC domain deletion compromises ATM protein stability, lymphocyte development, and promotes lymphomagenesis

Project description:ATM kinase is a master regulator of the DNA damage response and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in Phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. Here we show that in mouse models, knock-in ATM-R3057X (AtmRX, corresponding to R3047X in human ATM) mutation severely compromises ATM protein stability, and causes T cell development and B cell immunoglobulin class switch recombination defects and infertility resembling ATM-null. The residual ATM R3057X protein retains minimal, yet functional measurable, DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in AtmRX/RX mice compared to Atm-/-. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that minimal ATM activity can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.

2020-12-31 | GSE162568 | GEO

FATC domain deletion compromises ATM protein stability, lymphocyte development, and promotes lymphomagenesis

Project description:FATC domain deletion compromises ATM protein stability, lymphocyte development, and promotes lymphomagenesis

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Internal deletion compromises the stability of dystrophin.

Project description:Duchenne muscular dystrophy (DMD) is a deadly and common childhood disease caused by mutations that disrupt dystrophin protein expression. Several miniaturized dystrophin/utrophin constructs are utilized for gene therapy, and while these constructs have shown promise in mouse models, the functional integrity of these proteins is not well described. Here, we compare the biophysical properties of full-length dystrophin and utrophin with therapeutically relevant miniaturized constructs using an insect cell expression system. Full-length utrophin, like dystrophin, displayed a highly cooperative melting transition well above 37°C. Utrophin constructs involving N-terminal, C-terminal or internal deletions were remarkably stable, showing cooperative melting transitions identical to full-length utrophin. In contrast, large dystrophin deletions from either the N- or C-terminus exhibited variable stability, as evidenced by melting transitions that differed by 20°C. Most importantly, deletions in the large central rod domain of dystrophin resulted in a loss of cooperative unfolding with increased propensity for aggregation. Our results suggest that the functionality of dystrophin therapeutics based on mini- or micro-constructs may be compromised by the presence of non-native protein junctions that result in protein misfolding, instability and aggregation.

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Stk40 deletion enhances c-Jun protein stability and compromises mesoderm differentiation

Project description:Serine/threonine kinase 40 (Stk40) was previously identified as a direct target gene of pluripotency-associated transcription factor Oct4 and its overexpression could facilitate differentiation of mouse embryonic stem cells (mESCs) towards the extraembryonic endoderm. Stk40-/- mice are lethal at the perinatal stage, displaying multiple organ failures. However, the molecular mechanisms underlying the physiological functions of Stk40 remain elusive. Here, we report that Stk40 ablation compromises the mesoderm differentiation from mESCs in vitro and in embryos. Mechanistically, Stk40 interacts with both mammalian constitutive photomorphogenic protein 1 (Cop1) and c-Jun, promoting degradation of c-Jun. Consequently, Stk40 knockout leads to c-Jun protein accumulation, which, in turn, might suppress the Wnt signaling activity and impair the mesoderm differentiation process. Overall, this study reveals that Stk40, together with Cop1, represent a novel axis for modulating c-Jun protein levels within an appropriate range during mesoderm differentiation from mESCs. Our finding provides new insight into the molecular mechanism regulating c-Jun protein stability and may have potential for managing related cellular disorders.

2019-05-14 | PXD012579 | Pride

Homeobox protein NKX2-3 modulates lymphocyte dynamics and promotes B-cell lymphomagenesis

Project description:Molecular cloning of a t(10;14)(q24;q32) from a B-cell lymphoma showed a recurrent breakpoint in homeobox NKX2-3 gene, which was highly expressed in comparison to non-expressing mature B lymphocytes. Epigenetically-mediated NKX2-3 over-expression was selectively found in patients with splenic marginal-zone lymphoma, MALT lymphoma and extranodal diffuse large-cell lymphoma. In young mice, restricted expression of NKX2-3 to lymphocytes activated multiple integrins (LFA-1, VLA-4, MAC-1), adhesion molecules (ICAM-1, MadCAM-1, L-selectin) and the chemokine receptor CXCR4 that enhanced their homing and migration to splenic tissues, whereby they were retained, progressively accumulating to form non-clonal tumors. At 18 months, B cells acquired genomic rearrangements and generated clonal B-cell lymphomas mirroring the spectrum of human NKX2-3-expressing tumors. Mouse and human lymphomas displaying NKX2-3 expression shared histopahological, genomic and molecular features, including canonical NF-KB activation. NF-KB inhibition reduced tumorigenecity of NKX2-3-positive lymphomas. Our study reveals that oncogenic NKX2-3 promotes B-cell lymphomagenesis by disturbing lymphocyte dynamics. Comparisson of global gene expression profiling between Emu-NKX2-3 transgenes mice and wild type mice.

2016-07-22 | E-GEOD-49356 | biostudies-arrayexpress

Homeobox protein NKX2-3 modulates lymphocyte dynamics and promotes B-cell lymphomagenesis

2016-07-22 | GSE49356 | GEO

Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics.

Project description:NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-?B and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas.

| S-EPMC4911677 | biostudies-literature

Plasmodium vivax infection compromises reticulocyte stability.

Project description:The structural integrity of the host red blood cell (RBC) is crucial for propagation of Plasmodium spp. during the disease-causing blood stage of malaria infection. To assess the stability of Plasmodium vivax-infected reticulocytes, we developed a flow cytometry-based assay to measure osmotic stability within characteristically heterogeneous reticulocyte and P. vivax-infected samples. We find that erythroid osmotic stability decreases during erythropoiesis and reticulocyte maturation. Of enucleated RBCs, young reticulocytes which are preferentially infected by P. vivax, are the most osmotically stable. P. vivax infection however decreases reticulocyte stability to levels close to those of RBC disorders that cause hemolytic anemia, and to a significantly greater degree than P. falciparum destabilizes normocytes. Finally, we find that P. vivax new permeability pathways contribute to the decreased osmotic stability of infected-reticulocytes. These results reveal a vulnerability of P. vivax-infected reticulocytes that could be manipulated to allow in vitro culture and develop novel therapeutics.

| S-EPMC7955053 | biostudies-literature

Transcriptional Control by the FATC Domain of Saccharomyces cerevisiae Tra1

Project description:Tra1 is a component of the Saccharomyces cerevisiae SAGA and NuA4 complexes and a member of the phosphatidylinositol 3-kinase (PI3K) related kinase family that contain a C- terminal PI3K domain followed by a ~ 35-residue FATC domain. We have characterized four alleles with single residue changes in the FATC domain. Of these tra1-L3733A had the most pronounced effects with phenotypes including temperature and cold sensitivity, and reduced growth in media containing ethanol, Calcofluor white, rapamycin, chloramphenicol and geneticin. Tra1-L3733A interacted at normal levels with components of the NuA4 and SAGA complexes, and did not significantly alter histone acetylation patterns. The tra1-L3733A allele resulted in two-fold or greater change in expression of approximately 11% of yeast genes in rich media. Of the 279 genes with increased expression, 175 were ribosomal subunits or involved in ribosomal function or biogenesis. Elevated levels of Pol I and Pol III transcripts were also observed. The phenotypes of the tra1-L3733A overlapped with but were not identical to strains containing deletions of SAGA or NuA4 components or with strains containing mutations in the PI3K domain. Our finding that the double mutant allele, tra1-SRR3413/L3733A with alterations in the PI3K and FATC domains, resulted in wild type growth, suggests a model whereby the FATC domain negatively regulates the activity of the PI3K domain. Expression of genes involved in ribosome biosynthesis, other than the ribosomal subunits themselves, returned to near normal levels in the double mutant strain. We also characterized tra1-G3745, which contains an additional glycine residue following the normal C-terminal phenylalanine. This allele did not support viability and showed severe dominant negative effects. In contrast to what was observed for tra1-L3733A, tra1-G4745 resulted in decreased expression of genes required for ribosome biogenesis and did not interact with Esa1 or Spt7.

2011-09-20 | GSE13561 | GEO

Mutational analysis of the C-terminal FATC domain of Saccharomyces cerevisiae Tra1.

Project description:Tra1 is a component of the Saccharomyces cerevisiae SAGA and NuA4 complexes and a member of the PIKK family, which contain a C-terminal phosphatidylinositol 3-kinase-like (PI3K) domain followed by a 35-residue FATC domain. Single residue changes of L3733A and F3744A, within the FATC domain, resulted in transcriptional changes and phenotypes that were similar but not identical to those caused by mutations in the PI3K domain or deletions of other SAGA or NuA4 components. The distinct nature of the FATC mutations was also apparent from the additive effect of tra1-L3733A with SAGA, NuA4, and tra1 PI3K domain mutations. Tra1-L3733A associates with SAGA and NuA4 components and with the Gal4 activation domain, to the same extent as wild-type Tra1; however, steady-state levels of Tra1-L3733A were reduced. We suggest that decreased stability of Tra1-L3733A accounts for the phenotypes since intragenic suppressors of tra1-L3733A restored Tra1 levels, and reducing wild-type Tra1 led to comparable growth defects. Also supporting a key role for the FATC domain in the structure/function of Tra1, addition of a C-terminal glycine residue resulted in decreased association with Spt7 and Esa1, and loss of cellular viability. These findings demonstrate the regulatory potential of mechanisms targeting the FATC domains of PIKK proteins.

| S-EPMC2943577 | biostudies-literature

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