Regulatory Potential of the RNA Processing Machinery: Implications for Human Disease

Carey, Kirstyn T.; Wickramasinghe, Vihandha O.

doi:10.1016/j.tig.2017.12.012

Cited by 35 publications

(32 citation statements)

References 97 publications

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“…They recognize mRNAs during early stages of biogenesis and transfer the mature, spliced mRNAs to the NXF1:NXT1 nuclear export factor, which facilitates their export to the cytoplasm through interactions with the FG repeats of nucleoporins. TREX is recruited to mRNAs during splicing (18). TREX-2 is based on a GANP scaffold to which PCID2, DSSI, ENY2 and CETN2/3 bind (10).…”

Section: Introductionmentioning

confidence: 99%

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Woldegebriel

Kvist

Andersson

et al. 2020

Human Molecular Genetics

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Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.

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Section: Introductionmentioning

confidence: 99%

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Woldegebriel

Kvist

Andersson

et al. 2020

Human Molecular Genetics

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“…Although the conventional view has been that dysregulated transcription and signaling are the drivers of cancer, it is clear that dysregulated RNA processing in its many forms (eg, RNA trafficking, translation, stability, splicing, etc) contributes to the oncogenic phenotype and is targetable in malignancies. 8,9 AML has already been characterized to have dysregulated RNA processing, including elevated export of RNAs that support malignancy, increased translation, and dysregulated splicing, and these processes can be targeted in patients corresponding to clinical benefit. [8][9][10] The report by Beauchamp et al provides novel insights into the mechanisms that can dysregulate translation and transcription in AML and provides means to exploit these to identify next-generation strategies to target these processes in the clinic.…”

Section: Rictormentioning

confidence: 99%

“…8,9 AML has already been characterized to have dysregulated RNA processing, including elevated export of RNAs that support malignancy, increased translation, and dysregulated splicing, and these processes can be targeted in patients corresponding to clinical benefit. [8][9][10] The report by Beauchamp et al provides novel insights into the mechanisms that can dysregulate translation and transcription in AML and provides means to exploit these to identify next-generation strategies to target these processes in the clinic. The landmark study published in 2000 by Döhner and coworkers demonstrated that 80% of CLL cases could be risk stratified based on the presence of 4 recurrent abnormalities detectable by fluorescence in situ hybridization (FISH) analysis performed on interphase (nondividing) nuclei: del(13)(q14.1), trisomy 12, del(11)(q22-23), and del(17)(p13.1).…”

Section: Rictormentioning

confidence: 99%

CDK9 and mTOR: trading places

Borden

2019

Blood

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In this issue of Blood, Beauchamp et al 1 reveal that the kinase CDK9, typically associated with transcriptional elongation, 2 directly modulates translation through coopting components of the major translational regulatory complex mammalian target of rapamycin (mTOR). 3,4 These studies represent a major shift from the current paradigm; specifically, this work demonstrates that other kinases can coopt mTOR cofactors in order to modulate not only translation but also transcription as well as positioning CDK9 as an RNA processing cofactor. 10. Assouline S, Culjkovic B, Cocolakis E, et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-ofprinciple clinical trial with ribavirin.

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“…RNA processing factors function in intron removal and regulate alternative splicing events (ASEs) of eukaryotic genes. Aberrant selective RNA processing, especially alternative splicing (AS), facilitates cancer development and progression via alterations in protein structure, nonsense‐mediated mRNA decay, DNA repair defects and genome instability 8,9 . In CRC, several RNA processing factors, including HNRNPLL , SRSF1 , SRSF3 and SRSF6 , have been shown to actively participate in tumour progression and have demonstrated prognostic value, indicating that genetic alterations affecting RNA splicing are associated with CRC pathogenesis 10‐13 .…”

Section: Introductionmentioning

confidence: 99%

RNA processing genes characterize RNA splicing and further stratify colorectal cancer

Zhou

Meng

et al. 2020

Cell Proliferation

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Objectives Due to the limited evaluation of the prognostic value of RNA processing genes (RPGs), which are regulators of alternative splicing events (ASEs) that have been shown to be associated with tumour progression, this study sought to determine whether colorectal cancer (CRC) could be further stratified based on the expression pattern of RPGs. Materials and Methods The gene expression profiles of CRCs were collected from TCGA (training set) and three external validation cohorts, representing 1060 cases totally. Cox regression with least absolute shrinkage and selection operator (LASSO) penalty was used to develop an RNA processing gene index (RPGI) risk score. Kaplan‐Meier curves, multivariate Cox regression and restricted mean survival (RMS) analyses were harnessed to evaluate the prognostic value of the RPGI. Results A 22‐gene RPGI signature was developed, and its risk score served as a strong independent prognostic factor across all data sets when adjusted for major clinical variables. Moreover, ASEs for certain genes, such as FGFR1 and the RAS oncogene family, were significantly correlated with RPGI. Expression levels of genes involved in splicing‐ and tumour‐associated pathways were significantly correlated with RPGI score. Furthermore, a combination of RPGI with age and tumour stage resulted in significantly improved prognostic accuracy. Conclusions Our findings highlighted the prognostic value of RPGs for risk stratification of CRC patients and provide insights into specific ASEs associated with the development of CRC.

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Regulatory Potential of the RNA Processing Machinery: Implications for Human Disease

Cited by 35 publications

References 97 publications

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

CDK9 and mTOR: trading places

RNA processing genes characterize RNA splicing and further stratify colorectal cancer

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