NKAP acts with HDAC3 to prevent R-loop associated genome instability

Zhang, Xing; Duan, Jingwei; Li, Yang; Jin, Xiaoye; Wu, Cheng; Yang, Xiaohang; Lu, Weiguo; Ge, Wanzhong

doi:10.1038/s41418-023-01182-5

Cited by 6 publications

(6 citation statements)

References 77 publications

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“…We found that depletion of dNKAP results in chromosome abnormalities in Drosophila wing epithelial cells, although the frequency of cells with abnormal chromosomes and micronuclei is low. Interestingly, dNKAP -deficient cells show persistent accumulation of R-loops, which is consistent with our recent findings on human NKAP ( Zhang et al., 2023 ). R-loops can cause genome instability by inducing DNA damage or interfering with DNA replication ( Aguilera and Garcia-Muse, 2012 ; Naro et al., 2015 ).…”

Section: Discussionsupporting

confidence: 92%

“…This is partly attributed to an increased accumulation of R-loops during transcription ( Chan et al., 2014 ; Hamperl and Cimprich, 2014 ). We have recently found that human NKAP functions to prevent R-loop-associated genome instability ( Zhang et al., 2023 ). To determine whether depletion of dNKAP could result in R-loop accumulation and genome instability, we used an R-loop-specific monoclonal antibody, S9.6, for immunostaining.…”

Section: Resultsmentioning

confidence: 99%

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Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia

Guo,

Miao,

Liu

et al. 2023

Journal of Molecular Cell Biology

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Mutations or dysregulated expression of NF-kappaB activating protein (NKAP) family genes have been found in human cancers. How NKAP family gene mutations promote tumor initiation and progression remains to be determined. Here, we characterized dNKAP, the Drosophila homolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model. dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell invasive behavior, abnormal cell polarity, and cell adhesion defects. dNKAP knockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase (JNK)-dependent apoptosis and causes changes in cell proliferation in distinct cell populations. Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues. Furthermore, JNK signaling is essential for dNKAP depletion-mediated cell invasion. Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways. dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia

Guo,

Miao,

Liu

et al. 2023

Journal of Molecular Cell Biology

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“…Nkap protein participates in various biological processes in association with the Hdac3 protein 8,31,32 . The NKAP p.R330C, located in exon 8, modifies a highly conserved amino acid in the C‐terminal of Nkap protein.…”

Section: Discussionmentioning

confidence: 99%

“…NKAP , encoding the NF kappa B‐activating protein, is a highly conserved and widely expressed nucleoplasmic protein that plays critical roles in multiple biological processes, including transcriptional repressor, immune cells' proliferation and differentiation, RNA splicing and processing, and promoting survival of adult haematopoietic stem cells. 4 , 5 , 6 , 7 , 8 In 2019, Fiordaliso et al. reported for the first time that NKAP mutations in the C‐terminal region, including p.R330C, p.R330H, p.R333Q, p.I337T and p.R361Q, were associated with MRXSHD.…”

Section: Introductionmentioning

confidence: 99%

From phenotype to mechanism: Prenatal spectrum of NKAP mutation‐related disorder and its pathogenesis inducing congenital heart disease

Xu,

Gao,

et al. 2024

J Cellular Molecular Medi

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NKAP mutations are associated with Hackmann‐Di Donato‐type X‐linked syndromic intellectual developmental disorder (MRXSHD, MIM: #301039). Here, we elucidate the potential prenatal manifestation of NKAP mutation‐associated disorder for the first time, alongside revealing the relationship between NKAP mutations and congenital heart defect (CHD) in the Chinese population. An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD. Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level. Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1. Additionally, our research determined that NKAP p.R330C affected Nkap protein intra‐nuclear distribution, and binding with Hdac3. Summarily, our study strengthens NKAP mutations as a cause of CHD and prompts the reclassification of NKAP p.R330C as likely pathogenic, thereby establishing a prospective prenatal phenotypic spectrum that provides new insight into the prenatal diagnosis of CHD. Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra‐nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD.

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“…Dysregulation of NKAP has been linked to chromosome instability and DNA damage in previous work. Depletion of NKAP causes chromosome segregation defects and genome instability in HeLa cells (Li et al 2016) and increases the number of DNA damage foci in U2-OS osteosarcoma cells (Zhang et al 2023). Mutations in NKAP have recently been identified as a cause of a neurodevelopmental disorder in multiple unrelated families (Fiordaliso et al, 2019), emphasizing the importance of NKAP function in human cells.…”

Section: Discussionmentioning

confidence: 99%

GRAS1 non-coding RNA protects against DNA damage and cell death by binding and stabilizing NKAP

Su,

Trang,

Zhu

et al. 2023

Preprint

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Non-coding RNA (ncRNA) gene products are involved in diverse biological processes, but the biological mechanisms by which ncRNAs may regulate cell survival remain poorly understood. We found that the Growth Regulator Antisense (GRAS1) RNA transcript is a positive regulator of growth. Decreased levels of GRAS1 long non-coding RNA (lncRNA) caused DNA damage, cell death, and upregulated expression of genes associated with p53 signaling pathways. Extensive DNA damage occurred after GRAS1 knockdown, with multiple double strand breaks occurring in each cell. The number of cells arrested with low DNA content in sub-G1 phase increased significantly after GRAS1 knockdown. We used RNA antisense purification and mass spectrometry (RAP-MS) to identify the NF-κB activating protein (NKAP) as a direct protein interaction partner of GRAS1 lncRNA. NKAP protein levels decreased after GRAS1 knockdown, while mRNA levels were not affected. The decrease in NKAP protein after GRAS1 knockdown was blocked by proteasome inhibition. GRAS1 knockdown led to lipid peroxidation and overexpression of NKAP prevented the cell death effects of GRAS1 knockdown. NKAP overexpression protected against DNA damage in GRAS1 knockdown cells. We concluded that GRAS1 lncRNA binds and stabilizes NKAP to promote cell survival and protect against DNA damage and cell death.

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NKAP acts with HDAC3 to prevent R-loop associated genome instability

Cited by 6 publications

References 77 publications

Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia

Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia

From phenotype to mechanism: Prenatal spectrum of NKAP mutation‐related disorder and its pathogenesis inducing congenital heart disease

GRAS1 non-coding RNA protects against DNA damage and cell death by binding and stabilizing NKAP

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