RBMX family proteins connect the fields of nuclear RNA processing, disease and sex chromosome biology

Elliott, David J.; Dalgliesh, Caroline; Hysenaj, Gerald; Ehrmann, Ingrid

doi:10.1016/j.biocel.2018.12.014

Cited by 41 publications

(41 citation statements)

References 56 publications

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“…Mutations in RBMX were recently reported in papillary thyroid carcinoma cells resistant to vemurafenib [94], and knock-down of wild-type RBMX caused an increase of p-AKT protein level in naïve cancer cells. Several de novo mutations (G379R, Y357H, R339G, S337N, S303 frameshift) in RBMX that span the RNA-interacting domain of RBMX [92] were found in our study, but only one of them S303fs+/− was present in resistant melanoma cell lines with elevated activity of AKT (21_TRAR, 28_TRAR, 29_PLXR). The other four mutations were also acquired by 29_TRAR, but enhanced activity of AKT was not detected.…”

Section: Discussionmentioning

confidence: 49%

“…The activity of AKT signaling pathway was originally high in two drug-naïve cell lines and was elevated in a number of resistant cell lines. Interestingly, we have shown that activation of AKT in resistant cell lines might be connected with acquired mutations in a gene encoding RBMX, an RNA-binding protein protecting cells against DNA damage and acting as a tumor suppressor [92,93]. Mutations in RBMX were recently reported in papillary thyroid carcinoma cells resistant to vemurafenib [94], and knock-down of wild-type RBMX caused an increase of p-AKT protein level in naïve cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line-and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKT high resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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“…RBMX modulates multiple cellular processes. It has a highly conserved RNA-binding domain that enables its participation in pre-mRNA splicing (20). By associating with multiply splicing related proteins, RBMX forms the supraspliceosome that regulates the selection of alternative splice sites and facilities splicing of pre-mRNA (19,21).…”

mentioning

confidence: 99%

“…RBMX also participates in the regulation of gene transcription. In different cellular environments, RBMX may inhibit or activate gene transcription (20). For instance, RBMX is enriched within heterochromatin and interacts with transcriptionally modulated chromatin marker H3K9me3 to stop/slow down gene transcription during cellular reprogramming (24); conversely, through binding to the promoter of the sterol regulatory element-binding protein 1c (SREBP-1c) gene, RBMX activates transcription of the SREBP-1c gene in response to a high-fructose diet (25,26).…”

mentioning

confidence: 99%

X-Linked RNA-Binding Motif Protein Modulates HIV-1 Infection of CD4 ⁺ T Cells by Maintaining the Trimethylation of Histone H3 Lysine 9 at the Downstream Region of the 5′ Long Terminal Repeat of HIV Proviral DNA

Jiang

Sun

et al. 2020

mBio

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Reversible repression of HIV-1 5′ long terminal repeat (5′-LTR)-mediated transcription represents the main mechanism for HIV-1 to maintain latency. Identification of host factors that modulate LTR activity and viral latency may help develop new antiretroviral therapies. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are known to regulate gene expression and possess multiple physiological functions. hnRNP family members have recently been identified as the sensors for viral nucleic acids to induce antiviral responses, highlighting the crucial roles of hnRNPs in regulating viral infection. A member of the hnRNP family, X-linked RNA-binding motif protein (RBMX), has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5′-LTR-driven transcription of viral genome in CD4+ T cells. Mechanistically, RBMX binds to HIV-1 proviral DNA at the LTR downstream region and maintains the repressive trimethylation of histone H3 lysine 9 (H3K9me3), leading to a blockage of the recruitment of the positive transcription factor phosphorylated RNA polymerase II (RNA pol II) and consequential impediment of transcription elongation. This RBMX-mediated modulation of HIV-1 transcription maintains viral latency by inhibiting viral reactivation from an integrated proviral DNA. Our findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies. IMPORTANCE HIV-1 latency featuring silence of transcription from HIV-1 proviral DNA represents a major obstacle for HIV-1 eradication. Reversible repression of HIV-1 5′-LTR-mediated transcription represents the main mechanism for HIV-1 to maintain latency. The 5′-LTR-driven HIV gene transcription can be modulated by multiple host factors and mechanisms. The hnRNPs are known to regulate gene expression. A member of the hnRNP family, RBMX, has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5′-LTR-driven transcription of viral genome in CD4+ T cells and maintains viral latency. These findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

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“…Data supports a direct role for RBMX in preventing DNA damage occurring at DNA replication forks stalled at repetitive DNA sequences (15,16). During replication stress, Replication Protein A (RPA) binds to single stranded DNA at stalled replication forks, leading to ATR activation by parallel pathways that depend on the protein kinases ETAA1 and TOPB1 respectively (17).…”

Section: Introductionmentioning

confidence: 89%

RBMX enables productive RNA processing of ultra-long exons important for genome stability

Luzzi

Hysenaj

Siachisumo

et al. 2020

Preprint

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Previously we showed that the germline-specific RNA binding protein RBMXL2 is essential for male meiosis where it represses cryptic splicing patterns (1). Here we find that its ubiquitously expressed paralog RBMX helps underpin human genome stability by preventing non-productive splicing. In particular, RBMX blocks selection of aberrant splice and polyadenylation sites within some ultra-long exons that would interfere with genes needed for normal replication fork activity. Target exons include within the ETAA1 (Ewings Tumour Associated 1) gene, where RBMX collaborates with its interaction partner Tra2β to enable full-length exon inclusion by blocking selection of an aberrant 3’ splice site. Our data reveal a novel group of RNA processing targets potently repressed by RBMX, and help explain why RBMX is associated with gene expression networks in cancer, replication and sensitivity to genotoxic drugs.

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RBMX family proteins connect the fields of nuclear RNA processing, disease and sex chromosome biology

Cited by 41 publications

References 56 publications

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

X-Linked RNA-Binding Motif Protein Modulates HIV-1 Infection of CD4 ⁺ T Cells by Maintaining the Trimethylation of Histone H3 Lysine 9 at the Downstream Region of the 5′ Long Terminal Repeat of HIV Proviral DNA

RBMX enables productive RNA processing of ultra-long exons important for genome stability

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RBMX family proteins connect the fields of nuclear RNA processing, disease and sex chromosome biology

Cited by 41 publications

References 56 publications

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

X-Linked RNA-Binding Motif Protein Modulates HIV-1 Infection of CD4 + T Cells by Maintaining the Trimethylation of Histone H3 Lysine 9 at the Downstream Region of the 5′ Long Terminal Repeat of HIV Proviral DNA

RBMX enables productive RNA processing of ultra-long exons important for genome stability

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Resources

About

X-Linked RNA-Binding Motif Protein Modulates HIV-1 Infection of CD4 ⁺ T Cells by Maintaining the Trimethylation of Histone H3 Lysine 9 at the Downstream Region of the 5′ Long Terminal Repeat of HIV Proviral DNA