MCM3AP Is Transcribed from a Promoter within an Intron of the Overlapping Gene for GANP

Wickramasinghe, Vihandha O.; McMurtrie, Paul I.A.; Marr, Jackie; Amagase, Yoko; Main, Sarah; Mills, Anthony D.; Laskey, Ronald A.; Takei, Yoshiaki

doi:10.1016/j.jmb.2010.12.035

Cited by 16 publications

(17 citation statements)

References 15 publications

(30 reference statements)

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“…S7). However, since full‐length GANP(P443S) protein was not detectable (data not shown), it is conceivable that caspase‐mediated cleavage raised the level of HR‐stimulatory C‐terminal fragments mimicking MCM3AP [Wickramasinghe et al., ]. Altogether, elevated full‐length GANP/MCM3AP ratios in patient cells and WT‐GANP expressing parental cells represent a possible explanation for the observed HR decreases.…”

Section: Resultsmentioning

confidence: 97%

“…Re‐expression of WT‐GANP and downregulation of endogenous mutant GANP rescue the HR defect and DNA damage processing defect in patient‐derived cells. A : Schematic drawing of the GANP and MCM3AP protein structures encoded by the gene MCM3AP indicating the position of the aa exchange in the patient by an arrow (→) [modified from Wickramasinghe et al., ]. B : Expression of endogenous GANP and MCM3AP.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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“…Strangely, MCM3AP is transcribed from a promoter within an intron of GANP and has an unrelated function within the nucleus 104 . These features are consistent with the spatial distribution of GANP, which is concentrated at the nuclear envelope but is also present throughout the nucleus 12,56,105 .…”

Section: Non-homologous End Joiningmentioning

confidence: 99%

Control of mammalian gene expression by selective mRNA export

Wickramasinghe

Laskey

2015

Nat Rev Mol Cell Biol

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185

169

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Nuclear export of mRNAs is a crucial step in the regulation of gene expression, linking transcription in the nucleus to translation in the cytoplasm. Although important components of the mRNA export machinery are well characterized, such as transcription-export complexes TREX and TREX-2, recent work has shown that, in some instances, mammalian mRNA export can be selective and can regulate crucial biological processes such as DNA repair, gene expression, maintenance of pluripotency, haematopoiesis, proliferation and cell survival. Such findings show that mRNA export is an unexpected, yet potentially important, mechanism for the control of gene expression and of the mammalian transcriptome.

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“…A shorter isoform of GANP, GANP/MCM3AP (ref. 37), is likely to encode an 80-kDa protein associated with MCM3 of the DNA helicase MCM-complex composed of MCM2-MCM7 (refs 28, 38) and possesses HAT activity. Based on the Sac3-homology domain, GANP has been shown to play important roles in the mRNA export of mammalian cells3539.…”

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confidence: 99%

GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy

et al. 2013

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Somatic hypermutation in B cells is initiated by activation-induced cytidine deaminase-catalyzed C→U deamination at immunoglobulin variable regions. Here we investigate the role of the germinal centre-associated nuclear protein (GANP) in enhancing the access of activation-induced cytidine deaminase (AID) to immunoglobulin variable regions. We show that the nuclear export factor GANP is involved in chromatin modification at rearranged immunoglobulin variable loci, and its activity requires a histone acetyltransferase domain. GANP interacts with the transcription stalling protein Spt5 and facilitates RNA Pol-II recruitment to immunoglobulin variable regions. Germinal centre B cells from ganp-transgenic mice showed a higher AID occupancy at the immunoglobulin variable region, whereas B cells from conditional ganp-knockout mice exhibit a lower AID accessibility. These findings suggest that GANP-mediated chromatin modification promotes transcription complex recruitment and positioning at immunoglobulin variable loci to favour AID targeting.

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MCM3AP Is Transcribed from a Promoter within an Intron of the Overlapping Gene for GANP

Cited by 16 publications

References 15 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

Control of mammalian gene expression by selective mRNA export

GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy

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