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.v95.7.2321.007k33_2321_2328

Cited by 6 publications

(4 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We hypothesized that one or several RNA processing or export factors might be recruited to the NPC in TPR-dependent manner in order to perform their function. To address this, we processed NPC-enriched protein extracts by mass spectrometry and found a reduction of GANP 35 and PCID2 subunits of TREX-2 complex in TPR-depleted cells but not in NUP153- or NUP50-depleted cells (Fig. 3c and Supplementary Data 1 ).…”

Section: Resultsmentioning

confidence: 99%

Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

et al. 2020

View full text Add to dashboard Cite

Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocytoplasmic trafficking, including genome organization and gene expression. This multi-faceted nature and the slow turnover of NPC components complicates investigations of how individual nucleoporins act in these diverse processes. To address this question, we apply an Auxin-Induced Degron (AID) system to distinguish roles of basket nucleoporins NUP153, NUP50 and TPR. Acute depletion of TPR causes rapid and pronounced changes in transcriptomic profiles. These changes are dissimilar to shifts observed after loss of NUP153 or NUP50, but closely related to changes caused by depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. Moreover, TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) to NPCs and results in abnormal RNA transcription and export. Our findings demonstrate a unique and pivotal role of TPR in gene expression through TREX-2- and/or NXF1-dependent mRNA turnover.

show abstract

Section: Resultsmentioning

confidence: 99%

Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

et al. 2020

View full text Add to dashboard Cite

show abstract

“…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., ]. Indeed, GANP was shown to be required for efficient SHM and generation of high‐affinity B‐cells in mice [Sakaguchi et al., ; Kawatani et al., ] and to promote nuclear import of AID and binding to IgVH ‐regions by GANP–AID complex formation [Maeda et al., ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

“…By preparing mAbs against GC B cells, we found that a 210‐kDa nuclear protein is selectively up‐regulated in GC B cells upon immunization with TD‐Ag [30]. GANP is encoded by 29 exons in humans and mice.…”

Section: Ganp As a Key Molecule For Regulating Gc B Cell Differentiationmentioning

confidence: 99%

“…The middle portion of GANP is homologous to Saccharomyces cerevisiae Sac3 (suppressor of actin 3) of the THO/TREX2 complex constituting Sac3‐Thp1‐Cdc31‐Sus1 [34] with significant but low (25%) homology at the amino acid level (Sac3‐homology; SAC3/GANP/Nin1/mts3/eIF3p25) (Fig. 2) [30]. In the amino‐(N‐)terminal region, mammalian GANP possesses a unique region homologous to the nucleoporin component of nuclear pore complex [35].…”

Section: Ganp As a Key Molecule For Regulating Gc B Cell Differentiationmentioning

confidence: 99%

Molecular Mechanism of Immunoglobulin V‐Region Diversification Regulated by Transcription and RNA Metabolism in Antigen‐Driven B Cells

2011

View full text Add to dashboard Cite

The immune system produces specific antibodies (Ab) against any antigens (Ag) of exogenous and endogenous origins with a diverse repertoire of V‐region specificities. The primary V‐region repertoire is created by the rearrangement of immunoglobulin (Ig) V‐region, D‐ and J‐segments with the insertion of N‐ and P‐sequences during early B cell differentiation. Recent studies revealed that secondary diversification of the IgV‐region generated in the peripheral lymphoid organs plays a critical role in the generation of effective Ab production for protection from various pathogens. Naïve B cells that react with Ags initiate proliferation and differentiation in the follicular region and create the germinal centres (GCs), where activation‐induced cytidine deaminase (AID)‐dependent IgV‐region somatic hypermutation (SHM) and class‐switch recombination generate high‐affinity and class‐switched mature Ag‐specific B cells. Our studies have discovered a 210‐kDa nuclear protein, named GC‐associated nuclear protein (GANP) that is up‐regulated in GC B cells during the T cell–dependent (TD) immune responses. By studying mice with mutant forms of the ganp gene, we demonstrated that GANP is essential for the generation of high‐affinity B cells against TD‐Ag by affecting SHM at the IgV‐regions. GANP is associated with AID in the cytoplasm and the GANP/AID complex is recruited to the nucleus, specifically, the chromatin, and targeted selectively to the IgV‐region gene in B cells. GANP augments the access of AID towards IgV‐regions in B cells. Here, we review the role of GANP in acquired immunity through the detailed analysis of the molecular mechanism generating SHM specifically at IgV‐regions in B cells.

show abstract

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 6 publications

References 49 publications

Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

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

Molecular Mechanism of Immunoglobulin V‐Region Diversification Regulated by Transcription and RNA Metabolism in Antigen‐Driven B Cells

Contact Info

Product

Resources

About