International Journal of Molecular Sciences

Editorial

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4 pages, 196 KiB

Open AccessEditorial

RNA-Binding Proteins and Their Emerging Roles in Cancer: Beyond the Tip of the Iceberg

by John J. Murphy, Kalpana Surendranath and Radhakrishnan Kanagaraj

Int. J. Mol. Sci. 2023, 24(11), 9612; https://doi.org/10.3390/ijms24119612 - 1 Jun 2023

Cited by 2 | Viewed by 1052

Abstract

RNA-binding proteins (RBPs) represent a large family of proteins with an extensive array of roles that contribute to coordinating and directing multiple functions in RNA metabolism and transcription [...] Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

Research

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16 pages, 1673 KiB

Open AccessArticle

Dual Knockdown of Musashi RNA-Binding Proteins MSI-1 and MSI-2 Attenuates Putative Cancer Stem Cell Characteristics and Therapy Resistance in Ovarian Cancer Cells

by Maria T. Löblein, Isabel Falke, Hans Theodor Eich, Burkhard Greve, Martin Götte and Fabian M. Troschel

Int. J. Mol. Sci. 2021, 22(21), 11502; https://doi.org/10.3390/ijms222111502 - 25 Oct 2021

Cited by 15 | Viewed by 4731

Abstract

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian [...] Read more.

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy. Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

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20 pages, 4033 KiB

Open AccessArticle

RAD51 Inhibition Induces R-Loop Formation in Early G1 Phase of the Cell Cycle

by Zuzana Nascakova, Barbora Boleslavska, Vaclav Urban, Anna Oravetzova, Edita Vlachova, Pavel Janscak and Jana Dobrovolna

Int. J. Mol. Sci. 2021, 22(7), 3740; https://doi.org/10.3390/ijms22073740 - 3 Apr 2021

Cited by 7 | Viewed by 3660

Abstract

R-loops are three-stranded structures generated by annealing of nascent transcripts to the template DNA strand, leaving the non-template DNA strand exposed as a single-stranded loop. Although R-loops play important roles in physiological processes such as regulation of gene expression, mitochondrial DNA replication, or [...] Read more.

R-loops are three-stranded structures generated by annealing of nascent transcripts to the template DNA strand, leaving the non-template DNA strand exposed as a single-stranded loop. Although R-loops play important roles in physiological processes such as regulation of gene expression, mitochondrial DNA replication, or immunoglobulin class switch recombination, dysregulation of the R-loop metabolism poses a threat to the stability of the genome. A previous study in yeast has shown that the homologous recombination machinery contributes to the formation of R-loops and associated chromosome instability. On the contrary, here, we demonstrate that depletion of the key homologous recombination factor, RAD51, as well as RAD51 inhibition by the B02 inhibitor did not prevent R-loop formation induced by the inhibition of spliceosome assembly in human cells. However, we noticed that treatment of cells with B02 resulted in RAD51-dependent accumulation of R-loops in an early G1 phase of the cell cycle accompanied by a decrease in the levels of chromatin-bound ORC2 protein, a component of the pre-replication complex, and an increase in DNA synthesis. Our results suggest that B02-induced R-loops might cause a premature origin firing. Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

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14 pages, 2758 KiB

Open AccessArticle

MBNL2 Regulates DNA Damage Response via Stabilizing p21

by Jin Cai, Ningchao Wang, Guanglan Lin, Haowei Zhang, Weidong Xie, Yaou Zhang and Naihan Xu

Int. J. Mol. Sci. 2021, 22(2), 783; https://doi.org/10.3390/ijms22020783 - 14 Jan 2021

Cited by 12 | Viewed by 2640

Abstract

RNA-binding proteins are frequently dysregulated in human cancer and able to modulate tumor cell proliferation as well as tumor metastasis through post-transcriptional regulation on target genes. Abnormal DNA damage response and repair mechanism are closely related to genome instability and cell transformation. Here, [...] Read more.

RNA-binding proteins are frequently dysregulated in human cancer and able to modulate tumor cell proliferation as well as tumor metastasis through post-transcriptional regulation on target genes. Abnormal DNA damage response and repair mechanism are closely related to genome instability and cell transformation. Here, we explore the function of the RNA-binding protein muscleblind-like splicing regulator 2 (MBNL2) on tumor cell proliferation and DNA damage response. Transcriptome and gene expression analysis show that the PI3K/AKT pathway is enriched in MBNL2-depleted cells, and the expression of cyclin-dependent kinase inhibitor 1A (p21^CDKN1A) is significantly affected after MBNL2 depletion. MBNL2 modulates the mRNA and protein levels of p21, which is independent of its canonical transcription factor p53. Moreover, depletion of MBNL2 increases the phosphorylation levels of checkpoint kinase 1 (Chk1) serine 345 (S345) and DNA damage response, and the effect of MBNL2 on DNA damage response is p21-dependent. MBNL2 would further alter tumor cell fate after DNA damage, MBNL2 knockdown inhibiting DNA damage repair and DNA damage-induced senescence, but promoting DNA damage-induced apoptosis. Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

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Review

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20 pages, 3268 KiB

Open AccessReview

AU-Rich Element RNA Binding Proteins: At the Crossroads of Post-Transcriptional Regulation and Genome Integrity

by Ahmed Sidali, Varsha Teotia, Nadeen Shaikh Solaiman, Nahida Bashir, Radhakrishnan Kanagaraj, John J. Murphy and Kalpana Surendranath

Int. J. Mol. Sci. 2022, 23(1), 96; https://doi.org/10.3390/ijms23010096 - 22 Dec 2021

Cited by 21 | Viewed by 5831

Abstract

Genome integrity must be tightly preserved to ensure cellular survival and to deter the genesis of disease. Endogenous and exogenous stressors that impose threats to genomic stability through DNA damage are counteracted by a tightly regulated DNA damage response (DDR). RNA binding proteins [...] Read more.

Genome integrity must be tightly preserved to ensure cellular survival and to deter the genesis of disease. Endogenous and exogenous stressors that impose threats to genomic stability through DNA damage are counteracted by a tightly regulated DNA damage response (DDR). RNA binding proteins (RBPs) are emerging as regulators and mediators of diverse biological processes. Specifically, RBPs that bind to adenine uridine (AU)-rich elements (AREs) in the 3′ untranslated region (UTR) of mRNAs (AU-RBPs) have emerged as key players in regulating the DDR and preserving genome integrity. Here we review eight established AU-RBPs (AUF1, HuR, KHSRP, TIA-1, TIAR, ZFP36, ZFP36L1, ZFP36L2) and their ability to maintain genome integrity through various interactions. We have reviewed canonical roles of AU-RBPs in regulating the fate of mRNA transcripts encoding DDR genes at multiple post-transcriptional levels. We have also attempted to shed light on non-canonical roles of AU-RBPs exploring their post-translational modifications (PTMs) and sub-cellular localization in response to genotoxic stresses by various factors involved in DDR and genome maintenance. Dysfunctional AU-RBPs have been increasingly found to be associated with many human cancers. Further understanding of the roles of AU-RBP_S in maintaining genomic integrity may uncover novel therapeutic strategies for cancer. Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

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23 pages, 1527 KiB

Open AccessReview

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

by Maryam Nasiri-Aghdam, Texali C. Garcia-Garduño and Luis Felipe Jave-Suárez

Int. J. Mol. Sci. 2021, 22(20), 11056; https://doi.org/10.3390/ijms222011056 - 14 Oct 2021

Cited by 16 | Viewed by 3980

Abstract

Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA [...] Read more.

Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology. Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

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26 pages, 4309 KiB

Open AccessReview

The Emerging Role of Stress Granules in Hepatocellular Carcinoma

by Dobrochna Dolicka, Michelangelo Foti and Cyril Sobolewski

Int. J. Mol. Sci. 2021, 22(17), 9428; https://doi.org/10.3390/ijms22179428 - 30 Aug 2021

Cited by 8 | Viewed by 4016

Abstract

Stress granules (SGs) are small membrane-free cytosolic liquid-phase ordered entities in which mRNAs are protected and translationally silenced during cellular adaptation to harmful conditions (e.g., hypoxia, oxidative stress). This function is achieved by structural and functional SG components such as scaffold proteins and [...] Read more.

Stress granules (SGs) are small membrane-free cytosolic liquid-phase ordered entities in which mRNAs are protected and translationally silenced during cellular adaptation to harmful conditions (e.g., hypoxia, oxidative stress). This function is achieved by structural and functional SG components such as scaffold proteins and RNA-binding proteins controlling the fate of mRNAs. Increasing evidence indicates that the capacity of cells to assemble/disassemble functional SGs may significantly impact the onset and the development of metabolic and inflammatory diseases, as well as cancers. In the liver, the abnormal expression of SG components and formation of SG occur with chronic liver diseases, hepatocellular carcinoma (HCC), and selective hepatic resistance to anti-cancer drugs. Although, the role of SG in these diseases is still debated, the modulation of SG assembly/disassembly or targeting the expression/activity of specific SG components may represent appealing strategies to treat hepatic disorders and potentially cancer. In this review, we discuss our current knowledge about pathophysiological functions of SGs in HCC as well as available molecular tools and drugs capable of modulating SG formation and functions for therapeutic purposes. Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

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30 pages, 14258 KiB

Open AccessReview

R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

by Sidrit Uruci, Calvin Shun Yu Lo, David Wheeler and Nitika Taneja

Int. J. Mol. Sci. 2021, 22(16), 8850; https://doi.org/10.3390/ijms22168850 - 17 Aug 2021

Cited by 12 | Viewed by 8176

Abstract

Since their discovery, R-loops have been associated with both physiological and pathological functions that are conserved across species. R-loops are a source of replication stress and genome instability, as seen in neurodegenerative disorders and cancer. In response, cells have evolved pathways to prevent [...] Read more.

Since their discovery, R-loops have been associated with both physiological and pathological functions that are conserved across species. R-loops are a source of replication stress and genome instability, as seen in neurodegenerative disorders and cancer. In response, cells have evolved pathways to prevent R-loop accumulation as well as to resolve them. A growing body of evidence correlates R-loop accumulation with changes in the epigenetic landscape. However, the role of chromatin modification and remodeling in R-loops homeostasis remains unclear. This review covers various mechanisms precluding R-loop accumulation and highlights the role of chromatin modifiers and remodelers in facilitating timely R-loop resolution. We also discuss the enigmatic role of RNA:DNA hybrids in facilitating DNA repair, epigenetic landscape and the potential role of replication fork preservation pathways, active fork stability and stalled fork protection pathways, in avoiding replication-transcription conflicts. Finally, we discuss the potential role of several Chro-Mates (chromatin modifiers and remodelers) in the likely differentiation between persistent/detrimental R-loops and transient/benign R-loops that assist in various physiological processes relevant for therapeutic interventions. Full article

(This article belongs to the Special Issue RNA-Binding Proteins and Their Emerging Roles in Cancer)

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