Loss of the Fanconi anemia–associated protein NIPA causes bone marrow failure

Kreutmair, Stefanie; Erlacher, Miriam; Andrieux, Geoffroy; Istvànffy, Rouzanna; Mueller-Rudorf, Alina; Zwick, Melissa; Rückert, Tamina; Pantić, Milena; Poggio, Teresa; Shoumariyeh, Khalid; Mueller, Tony; Kawaguchi, Hiroyuki; Follo, Marie; Klingeberg, Cathrin; Wlodarski, Marcin W.; Baumann, Irith; Pfeifer, Dietmar; Kuliński, Michał; Rudelius, Martina; Lemeer, Simone; Küster, Bernhard; Dierks, Christine; Peschel, Christian; Cabezas-Wallscheid, Nina; Duque‐Afonso, Jesús; Zeiser, Robert; Cleary, Michael L.; Schindler, Detlev; Schmitt‐Graeff, Annette; Boerries, Melanie; Niemeyer, Charlotte M.; Oostendorp, Robert A.J.; Duyster, Justus; Illert, Anna Lena

doi:10.1172/jci126215

Cited by 9 publications

(8 citation statements)

References 81 publications

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“…In the case of Hs ZC3HC1, though, its NuBaID currently appears monogamous for only one stably to be bound protein, namely Hs TPR, also since other proteins formerly proposed as regular ZC3HC1 binding partners, like components of the SCF complex, CCNB1, and FANCD2 (e.g., Bassermann et al , 2005; Kreutmair et al , 2020), have been ruled out (Gunkel et al , 2021) or assessed as unlikely (Supplemental Figure S13). However, we do not exclude the possibility that some ZC3HC1 paralogs, like in plants, have established binding interfaces for stably interacting partners other than TPR that are yet unknown.…”

Section: Discussionmentioning

confidence: 99%

Nuclear basket protein ZC3HC1 and its yeast homolog Pml39p feature an evolutionary conserved bimodular construction essential for initial binding to NPC-anchored homologs of scaffold protein TPR

Gunkel¹,

Iino²,

Krull³

et al. 2022

Preprint

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Proteins ZC3HC1 and TPR are construction elements of the nuclear pore complex (NPC)-attached nuclear basket (NB). NB-location of ZC3HC1 depends on TPR already occurring NPC-anchored, whereas additional TPR polypeptides are appended to the NB by ZC3HC1. The current study examined the molecular properties of ZC3HC1 that enable it to bind to the NB and TPR. We report the identification and definition of a nuclear basket-interaction domain (NuBaID) of HsZC3HC1 comprising two similarly built modules, both essential for the binding to the NB's NPC-anchored HsTPR. Furthermore, we describe such a bimodular construction as evolutionarily conserved and exemplify the kinship of HsZC3HC1 by the NB- and DdTPR-interacting homolog of Dictyostelium discoideum and by characterizing protein Pml39 as the ZC3HC1 homolog in Saccharomyces cerevisiae. Among several properties shared by the different species' homologs, we unveil the integrity of the bimodular NuBaID of ScPml39p as being essential for binding to the yeast's NBs and its TPR homologs ScMlp1p and ScMlp2p, and we further present Pml39p as enabling interlinkage of Mlp1p subpopulations. In addition to phyla-specific features, we delineate the three species' common NuBaID as the characterizing structural entity of a one-of-a-kind protein found not in all but likely most taxa of the eukaryotic realm.

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Section: Discussionmentioning

confidence: 99%

Nuclear basket protein ZC3HC1 and its yeast homolog Pml39p feature an evolutionary conserved bimodular construction essential for initial binding to NPC-anchored homologs of scaffold protein TPR

Gunkel¹,

Iino²,

Krull³

et al. 2022

Preprint

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“…NIPA has recently been described as a crucial regulator of mitotic entry and bone marrow failure (35,42), but has not yet been analyzed in NPM-ALK-induced lymphomas, where it was initially found as an interaction partner of NPM-ALK. Ouyang et al have shown that NIPA interacts with NPM-ALK in a kinase-dependent manner and can protect Ba/F3 cells from apoptosis (31).…”

Section: Discussionmentioning

confidence: 99%

“…Flow cytometry analysis was performed as described (35). The BD LSR Fortessa (BD Biosciences, Heidelberg, Germany) was used for analysis.…”

Section: Flow Cytometry Analysismentioning

confidence: 99%

“…Interestingly, in the presence of NPM-ALK, STAT3, AKT, and ERK1/2 demonstrated regular phosphorylation and therefore activation independent of NIPA (Supplementary Figure 3A). Thus, as it has been shown previously that Nipa deficiency significantly reduces hematopoietic stem cell frequency after replication stress due to impaired DNA damage repair followed by apoptosis (35), we analyzed thymic lymphomas of Lck/Cre TG/wt Nipa wt/wt and Nipa flox/flox MSNAIE transplanted mice for stem cell markers. We indeed found a small but distinct lymphoma subpopulation characterized by expression signatures Lineage-negative (CD4 − CD8 − CD25 − CD44 − ), cKIT, and SCA1positive, which was significantly lower in Nipa ko/ko lymphoma cells, being only one-third of Nipa wt/wt cells (0.19% vs. 0.57%, p = 0.04, Figures 4A, C and Supplementary Figure 3B).…”

Section: Nipa Is Associated With "Stem-cell-like" Features Of T-lymph...mentioning

confidence: 99%

“…As a Fanconi anemia-associated protein, NIPA regulates the nuclear abundance of FANCD2, thereby making it essential for a functional DNA repair/Fanconi anemia/BRCA pathway. Aging or other replication stress triggers the decrease and functional decline of Nipa-deficient HSCs, resulting in complete bone marrow failure (35).…”

Section: Introductionmentioning

confidence: 99%

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NIPA (Nuclear Interaction Partner of ALK) Is Crucial for Effective NPM-ALK Mediated Lymphomagenesis

et al. 2022

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The NPM-ALK fusion kinase is expressed in 60% of systemic anaplastic large-cell lymphomas (ALCL). A Nuclear Interaction Partner of ALK (NIPA) was identified as a binding partner of NPM-ALK. To identify the precise role of NIPA for NPM-ALK-driven lymphomagenesis, we investigated various NPM-ALK+ cell lines and mouse models. Nipa deletion in primary mouse embryonic fibroblasts resulted in reduced transformation ability and colony formation upon NPM-ALK expression. Downregulating NIPA in murine NPM-ALK+ Ba/F3 and human ALCL cells decreased their proliferation ability and demonstrated synergistic effects of ALK inhibition and NIPA knockdown. Comprehensive in vivo analyses using short- and long-latency transplantation mouse models with NPM-ALK+ bone marrow (BM) revealed that Nipa deletion inhibited NPM-ALK-induced tumorigenesis with prolonged survival and reduced spleen colonies. To avoid off-target effects, we combined Nipa deletion and NPM-ALK expression exclusively in T cells using a lineage-restricted murine ALCL-like model resembling human disease: control mice died from neoplastic T-cell infiltration, whereas mice transplanted with Lck-CreTG/wtNipaflox/flox NPM-ALK+ BM showed significantly prolonged survival. Immunophenotypic analyses indicated a characteristic ALCL-like phenotype in all recipients but revealed fewer “stem-cell-like” features of Nipa-deficient lymphomas compared to controls. Our results identify NIPA as a crucial player in effective NPM-ALK-driven ALCL-like disease in clinically relevant murine and cell-based models.

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Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions

Shafqat

Tariq

Parnes

et al. 2021

Hematology/Oncology and Stem Cell Therapy

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Loss of the Fanconi anemia–associated protein NIPA causes bone marrow failure

Cited by 9 publications

References 81 publications

Nuclear basket protein ZC3HC1 and its yeast homolog Pml39p feature an evolutionary conserved bimodular construction essential for initial binding to NPC-anchored homologs of scaffold protein TPR

Nuclear basket protein ZC3HC1 and its yeast homolog Pml39p feature an evolutionary conserved bimodular construction essential for initial binding to NPC-anchored homologs of scaffold protein TPR

NIPA (Nuclear Interaction Partner of ALK) Is Crucial for Effective NPM-ALK Mediated Lymphomagenesis

Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions

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