The Role of RNA-Binding Proteins in Hematological Malignancies
Abstract
:1. Introduction
2. RNA-Binding Proteins
3. mRNA Regulation by RBPs
3.1. mRNA 5′ Capping
3.2. Splicing of Pre-mRNAs
3.3. Cleavage and 3′ End Formation
3.4. mRNA Export
3.5. mRNA Stability
3.6. Translation
3.7. RNA Editing
4. RNA-Binding Proteins in Hematological Malignancies
4.1. RBM39–mRNA Splicing
4.2. Musashi Proteins (MSI1 and MSI2)-mRNA Translation
4.3. IGF2BP3–mRNA Localization, mRNA Stability and mRNA Degradation
4.4. hnRNP K–mRNA Localization, Transcription, Translation and Splicing
5. Discussion
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Type of Binding Domain | Structure Interface | Interaction between RBP and RNA | Nucleic Acid Affinity | RBPs Containing RBDs |
---|---|---|---|---|
KH type I (hnRNP K homology type I) | Structure approximately 70 amino acids long. It typically adopts βααββα, forming by a β-sheet composed of 3 antiparallel β-strands and 3 α-helices [27,28] | Four single-stranded nucleotides are recognized by the invariant Gly–X–X–Gly motif, the near helices, and the β-strand that follows α2 (type I) | C-rich ssDNA and ssRNA [27,28] | hnRNP K [29], Nus A [30], SF1 [31], Nova-2 [32] |
KH type II (hnRNP K homology type II) | Structure approximately 70 amino acids long. It is displayed as a αββααβ [27] | Same as KH I, where four single-stranded nucleotides are recognized by α3 (instead of α2 as in KH I) | C-rich ssDNA and ssRNA [27,28] | hnRNP K [29], Nus A [30], SF1 [31], Nova-2 [32] |
KH type III (hnRNP K homology type III) | Structure approximately 75-80 amino acids long. It typically adopts a spatial configuration of βααββα, forming a 3-stranded β-sheet held against a 3-helix cluster [27] | Same as KH type I | C-rich ssDNA and ssRNA [27,28] | Nova-2 [33], hnRNP K [34] |
RRMs (RNA recognition motifs) | Structure approximately 80-90 amino acids long. It typically adopts topology of βαββαβ, forming a 4-stranded β-sheet and 2 α-helices [35] | Main interaction between the binding domain and RNA is mediated through the β-sheet | Polypyrimidine (mainly C- and U-rich sequences) ssRNA [35,36] | U2AF65 [36], nucleolin [37], SRp20 [38], hnRNP F [39], FOX1 [40], Musashi 1, Musashi 2 [41], RBM39 [42] |
ZnF (Zinc Fingers) | Structure approximately 30 amino acids long. It displays a ββα topology, forming a β-hairpin and an α-helix together with a Zn2+ ion [43] | Binding to nucleic acids through the α-helix | dsDNA, ssRNA, dsRNA [44] | MBNL1 [44], TFIIIA [45], ZRANB2 [46] |
dsRBDs (double-stranded RNA binding domains) | Structure approximately 65-70 amino acids long. It typically adopts a αβββα topology, where 2 α-helices are packed along a 3-stranded anti-parallel β-sheet [47] | Binding to dsRNA backbone through α2 and the β1- β2 loop. Additional interactions occur through the α1 | dsRNA [47] | ADAR1 [48], Dicer [49] |
DEAD-box | Structure approximately 300-400 amino acids long. It adopts a βαββαβ topology, forming a 4-stranded β-sheet and 2 α-helices, similar to RRM binding domains [50] | Helicase core binds to the backbone of the RNA, without contact with the nucleotides | Polypyrimidine ssRNA [50] | eIF4A1/DDX2 [51], p68 [52], p72 [53] |
PUF (Pumilio-fem-3 binding factor) | Structure approximately 6-8 tandem copies of a 35 amino acids long sequence. It adopts a topology of 3 α- helices, forming a triangle [54] | Binding to RNA is through the α 2 in each tandem repeat | ssRNA [55] | PUM1, PUM2 [55] |
SAM (Sterile alpha motif) | Structure approximately 150-160 amino acids long. It displays a topology of 6 α-helices, packed by a hydrophobic core [56] | Traditionally known to bind protein, but has recently been shown to bind RNA | Hairpin RNA [56] | p63, p73 [57], p73, EPHA2 [58] |
RBP | RNA Binding Motif | Role in Normal Hematopoiesis | Related Hematological Malignancies |
---|---|---|---|
ADAR1 | dsRBD [48] | Regulation of HSCs differentiation via base editing activity | Enhanced editing activity in CML, increasing self-renewal capacity |
DDX3X, DDX5 | DEAD Box [51] | Essential for the innate immune response and normal hematopoiesis | Frequently mutated in hematological malignances, and upregulated upon Imatinib treatment |
DDX21 | DEAD Box [51] | HSCs self-renewal | Increases leukemia stem cell proliferation in AML |
EIF4E | DEAD Box | Transcription factor, cell differentiation [94] | Blockage of myeloid differentiation, leading to leukemogenesis |
hnRNP K | KH1, KH2, KH3 [95] | DNA damage response and cell cycle arrest [96,97] | Deletion in AML [98,99,100,101], overexpression in CML [102,103], oncogen in DLBCL [22] and MM [104] |
IGF2BP3 | RRM, KH [105] | Self-renewal of HSCs [106] | B-ALL cell survival [106], MLL [107], and therapeutic resistance in MM [108] |
MSI2 | RRM [41] | Self-renewal of HSCs [109] | Upregulated in most hematological malignancies and associated to poor prognosis [110,111] |
RBM39 | RRM [42] | Part of the spliceosome [112] | AML malignant cell growth and maintenance [113], as well as myeloma progression [114] |
SRSF2 | RRM [38] | Essential for myeloid hematopoiesis [115] | Mutations associated to poor survival in MDS [115] |
SF3B1 | RRM [36] | HSCs homeostasis [116] | Mutations associated with MDS [116] |
ZFP36 | ZnF [43] | Hematopoiesis and cell differentiation [117] | Loss of function leads to leukemogenesis [117] |
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Aguilar-Garrido, P.; Otero-Sobrino, Á.; Navarro-Aguadero, M.Á.; Velasco-Estévez, M.; Gallardo, M. The Role of RNA-Binding Proteins in Hematological Malignancies. Int. J. Mol. Sci. 2022, 23, 9552. https://doi.org/10.3390/ijms23179552
Aguilar-Garrido P, Otero-Sobrino Á, Navarro-Aguadero MÁ, Velasco-Estévez M, Gallardo M. The Role of RNA-Binding Proteins in Hematological Malignancies. International Journal of Molecular Sciences. 2022; 23(17):9552. https://doi.org/10.3390/ijms23179552
Chicago/Turabian StyleAguilar-Garrido, Pedro, Álvaro Otero-Sobrino, Miguel Ángel Navarro-Aguadero, María Velasco-Estévez, and Miguel Gallardo. 2022. "The Role of RNA-Binding Proteins in Hematological Malignancies" International Journal of Molecular Sciences 23, no. 17: 9552. https://doi.org/10.3390/ijms23179552