A novel nuclear phosphoprotein, GANP, is up-regulated in centrocytes of the germinal center and associated with MCM3, a protein essential for DNA replication

Kuwahara, K.; Yoshida, Mikoto; Kondo, Eisaku; Sakata, Atsuko; Watanabe, Yuko; Abe, Eiji; Kouno, Yoshiyasu; Tomiyasu, Shinjirou; Fujimura, Satoru; Tokuhisa, Takeshi; Kimura, Hiroshi; Ezaki, Taichi; Sakaguchi, Nobuo

doi:10.1182/blood.v95.7.2321

Cited by 61 publications

(47 citation statements)

References 49 publications

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“…Of note with regard to the patient´s aberrant Ig class distribution, GANP has been described to become selectively upregulated in GC B-cells upon thymus-dependent antigen immunization. In GCs, AID-dependent somatic hypermutation (SHM) and CSR generate high-affinity and class-switched mature antigen-specific B-cells [Kuwahara et al, 2000]. Indeed, GANP was shown to be required for efficient SHM and generation of high-affinity B-cells in mice [Sakaguchi et al, 2002;Kawatani et al, 2005] and to promote nuclear import of AID and binding to IgVH-regions by GANP-AID complex formation [Maeda et al, 2010].…”

Section: Discussionmentioning

confidence: 99%

MCM3APandPOMPMutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child

et al. 2015

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Immunodeficiency patients with DNA repair defects exhibit radiosensitivity and proneness to leukemia/lymphoma formation. Though progress has been made in identifying the underlying mutations, in most patients the genetic basis is unknown. Two de novo mutated candidate genes, MCM3AP encoding germinal center-associated nuclear protein (GANP) and POMP encoding proteasome maturation protein (POMP), were identified by whole-exome sequencing (WES) and confirmed by Sanger sequencing in a child with complex phenotype displaying immunodeficiency, genomic instability, skin changes, and myelodysplasia. GANP was previously described to promote B-cell maturation by nuclear targeting of activation-induced cytidine deaminase (AID) and to control AID-dependent hyperrecombination. POMP is required for 20S proteasome assembly and, thus, for efficient NF-κB signaling. Patient-derived cells were characterized by impaired homologous recombination, moderate radio- and cross-linker sensitivity associated with accumulation of damage, impaired DNA damage-induced NF-κB signaling, and reduced nuclear AID levels. Complementation by wild-type (WT)-GANP normalized DNA repair and WT-POMP rescued defective NF-κB signaling. In conclusion, we identified for the first time mutations in MCM3AP and POMP in an immunodeficiency patient. These mutations lead to cooperative effects on DNA recombination and damage signaling. Digenic/polygenic mutations may constitute a novel genetic basis in immunodeficiency patients with DNA repair defects.

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Section: Discussionmentioning

confidence: 99%

MCM3APandPOMPMutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child

et al. 2015

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“…For instance, we have observed an interaction between IE86 and the cellular protein GANP/ MCM3AP. This cellular protein functions as an acetylase of the MCM3 component of the MCM complex and serves to block the initiation of DNA replication but, crucially, not the loading of MCMs [93][94][95][96]. This suggests a model in which IE86 recruits GANP/MCM3AP to cellular origins and causes the untimely acetylation of MCM3, thus inhibiting cellular replication (Bain M and Sinclair J., unpublished observations).…”

Section: The Effects Of the Major Ie Proteinsmentioning

confidence: 99%

The S phase of the cell cycle and its perturbation by human cytomegalovirus

Bain

2007

Reviews in Medical Virology

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Human cytomegalovirus (HCMV) is a complex human herpesvirus that is known to productively infect a wide range of cell types. In addition, it has been suggested to contribute to some proliferative disorders, particularly atherosclerosis. Consistent with this, a number of studies have shown that HCMV profoundly affects normal cell cycle control. Specifically, the virus can stimulate early entry into S phase thus ensuring adequate resources for viral DNA replication. Importantly, however, the virus concomitantly inhibits potentially competing cellular DNA synthesis allowing cellular precursors to be used for viral but not cellular DNA replication. The mechanisms by which HCMV perturbs S phase entry involve interactions between the virus and the cellular replication machinery such that formation of competent pre-replication complexes (Pre-RC) at cellular origins of replication is restricted in infected cells.

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“…In mammals, however, little is known about the regulation of DNA recombination via Sac3-like molecule(s). A mammalian homologue GANP is expressed in GC B-cells after immunization with T-cell-dependent Ags (Kuwahara et al . 2000).…”

Section: Introductionmentioning

confidence: 99%

GANP suppresses DNA recombination, measured by direct‐repeat β‐galactosidase gene construct, but does not suppress the type of recombination applying to immunoglobulin genes in mammalian cells

et al. 2007

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Immunoglobulin V-region somatic hypermutation and C-region class-switch recombination are initiated by activation-induced cytidine deaminase (AID) in B-cells. AID-induced DNA damage at the immunoglobulin S-region is known to be repaired by non-homologous end-joining, but repair mechanisms at the V-region remain to be elucidated. In Saccharomyces cerevisiae , DNA homologous recombination is regulated by the expression of Sac3, involved in actin assembly, cell cycle transition and mRNA metabolism. Here, we demonstrate that the Sac3-homologue GANP suppresses DNA recombination in a direct-repeat β β β β -galactosidase gene construct in mammalian cells. Homozygous ganp gene knockout is embryonic lethal in mice. Embryonic fibroblasts immortalized from hetero-deficient ganp +/-mice showed more DNA recombination than wild-type. In contrast, over-expression of GANP suppressed either spontaneous DNA recombination or that caused by the introduction of aid cDNA into NIH3T3 cells (susceptible to I-sce I restriction enzyme cleavage but not to RAG-mediated immunoglobulin gene recombination). GANP suppresses the DNA recombination not only on the extrachromosomal DNA construct but also on the integrated DNA. The Sac3-homology portion is necessary for the suppressive activity, but the truncated carboxyl terminal MCM3-binding/acetylating region adversely augmented DNA recombination, acting as a dominant negative form. Expression of full-length GANP is critical for suppression of DNA hyper-recombination in mammalian cells. IntroductionB-cells produced in the bone marrow undergo random rearrangements of immunoglobulin ( Ig ) gene segments such as V H -D H -J H and V L -J L to generate unique antigen (Ag) receptors. Naïve B-cells recruited into peripheral lymphoid organs encounter exogenous Ags and start to proliferate and differentiate with the help of Th cells in the lymphoid follicles in response to T-cell-dependent Ag. The Ag-driven B-cells undergo Ig gene V-region somatic hypermutation and class-switch recombination initiated by activation-induced cytidine deaminase (AID), generating DNA cleavages during transcription or DNA replication in germinal centers (GCs) (Honjo et al . 2002). DNA double-strand breaks (DSBs) occur in both Ig Vregions and S-regions , which are considered to be repaired by the different DNA repair mechanisms. In contrast to 1206the S-region, where DNA repair is undertaken by a nonhomologous end-joining repair (NHEJR) mechanism utilizing Ku70/Ku80, DNA-PKcs, XRCC4 and DNA ligase IV, DSB repair mechanisms at the V-region genes remained undetermined (Casellas et al . 1998;Manis et al . 1998;Meek et al . 2004;Rooney et al . 2004). DNA repair in many cells depends on homologous recombination (HR) creating single-strand DNA to anneal with the undamaged complementary strand of the paired allele during DNA replication (West 2003). HR rescues the DNA with various DNA polymerases by reading the complementary strand from the undamaged allele.In Saccharomyces cerevisiae, an inhibitor of actin assembly, Sac3, is critic...

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A novel nuclear phosphoprotein, GANP, is up-regulated in centrocytes of the germinal center and associated with MCM3, a protein essential for DNA replication

Cited by 61 publications

References 49 publications

MCM3APandPOMPMutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child

MCM3APandPOMPMutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child

The S phase of the cell cycle and its perturbation by human cytomegalovirus

GANP suppresses DNA recombination, measured by direct‐repeat β‐galactosidase gene construct, but does not suppress the type of recombination applying to immunoglobulin genes in mammalian cells

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