Alu RNA and their roles in human disease states

Figures & data

Figure 1. Schematic of LINE1-mediated retrotransposition of alu elements as described by Dewannieux et al. [6]. Ribosome, DNA, RNA, and protein molecules are depicted in black, green, red, and blue, respectively. a) LINE1 mRNA is translated generating the ORF2 protein which possesses reverse transcriptase and endonuclease activity; b) The alu element located in the genomic DNA is transcribed into an RNA which is bound by the SRP9/SRP14 heterodimer to localize it to the 40S ribosomal small subunit of the ribosome translating ORF2; c) positioning of the alu RNA relative to ORF2 allows for its reverse transcription and generation of an alu cDNA; d) the alu cDNA is trafficked by ORF2 back to the genomic DNA, where ORF2 both endonucleolytically cuts the genomic DNA and reintegrates the cDNA, forming a new alu DNA insert

Figure 2. Structural elements of alu RNA. a) alu element and associated genomic regulatory regions. RNA polymerase III promoter elements, A- and B-boxes are found on the left arm of alu elements. an internal polyadenylation tract separates the left and right arms. the right arm is differentiated from the left arm by a 31-nucleotide insertion. b) Secondary structure of an AluY RNA found on intron 4 of the $\alpha$-fetoprotein gene. the structure forms two distinct arms with an internal polyadenylation tract separating them. potential acceptor and donor splice sites found in the alu consensus sequence as described by Sorek et al. were adapted to the presented AluY RNA [35]. darkly shaded boxes behind nucleotides indicate potential donor splice sites (5ʹ-GC and 5ʹ-GU for sense strand, and 5ʹ-GC and 5ʹ-AC for antisense strand alu RNA). LIGHTLY shaded boxes behind nucleotides indicate potential acceptor splice sites (5ʹ-AG for sense strand and 5ʹ-CU for antisense strand alu RNA). (c) secondary structure of the 7SL or signal recognition particle RNA. the structure is segmented into two regions, the alu domain and the S domain. the alu domain is recognized by SRP9 and SRP14, while the S domain interacts with SRP19, SRP54, SRP68 and SRP72 in the signal recognition particle [86]. this figure was adapted from work from Häsler et al. [33,80]

Table 1. List of alu RNA impacting gene regulation and implicated in human diseases

Gene	Human Disease*	Alu Family**	Sequence Type	Mechanism	References
COL4A3	Alport Syndrome	Unclear	Intron	Cryptic Exon Alternative Splicing	[42]
COL4A5	Alport Syndrome	AluY	Intron	Cryptic Exon Alternative Splicing	[87]
ATM	Ataxia-Telangiectasia	AluSg	Intron	Cryptic Exon Alternative Splicing	[88]
CNTN1	Brain Cancer	AluY	Mature mRNA	Secondary Structure Directly Impacting Translation	[89]
MED13	Brain Cancer	Many	Intron	A-to-I Editing	[46]
BC200	Breast Cancer	AluJ	Non-Coding	Translation Impacting	[83,85]
BRCA1	Breast Cancer	AluSq2	Intron	A-to-I Editing	[47]
BRCA1	Breast Cancer	AluSx	Mature mRNA	Secondary Structure Directly Impacting Translation	[61,62]
MDM2	Breast Cancer	Unclear	Mature mRNA	Inverted Repeat Alu RNA	[90, 30]
MDM2	Breast Cancer	Many	Mature mRNA	Alu RNA Mediated mRNA Decay	[74]
MDM4	Breast Cancer	Many	Mature mRNA	Alu RNA Mediated mRNA Decay	[74]
PMM2	Congenital Disorders of Glycosylation-Ia Syndrome	AluJb	Intron	Cryptic Exon Alternative Splicing	[91]
DMD	Duchenne-Type Muscular Dystrophy	Unclear	Intron	Cryptic Exon Alternative Splicing	[92]
PDZK1	Gastric Cancer	AluSg	Mature mRNA	Secondary Structure Directly Impacting Translation	[93]
HIPK3	Gliomas	AluSz and AluSq2	Intron	Circular RNA	[54,55]
ZNF655	Gliomas	AluSg	Mature mRNA	Alu RNA Mediated mRNA Decay	[94]
OAT	Gyrate Atrophy	AluSx4	Intron	Cryptic Exon Alternative Splicing	[95]
F8	Haemophilia A	AluY	Intron	Cryptic Exon Alternative Splicing	[43]
PSMB2	Hepatocellular Carcinoma	AluSc and AluJb	Mature mRNA	Inverted Repeat Alu RNA	[66,67]
NOSIP	Hirschsprung’s Disease	AluSp	Mature mRNA	Secondary Structure Directly Impacting Translation	[93, 96]
PTS	Hyperphenylalaninemia	AluSq2	Intron	Cryptic Exon Alternative Splicing	[114]
LRRC56	Impaired Mucocillary Clearance	AluY	Mature mRNA	Secondary Structure Directly Impacting Translation	[93,115]
AKR1A1	Laryngeal Cancer	AluJo	Mature mRNA	Secondary Structure Directly Impacting Translation	[93,116])
XIAP	Leukaemias	Unclear	Mature mRNA	Inverted Repeat Alu RNA	[30, 117]
POLR3A	Leukodystrophy	AluSx	Intron	Cryptic Exon Alternative Splicing	[118]
1/2sbsRNA	Many	Many	Mature mRNA	Alu RNA Mediated mRNA Decay	[70]
C19MC	Many	Many	Intron	miRNA Sequence Sources	[50,52]
CYP20A1	Many	Many	Mature mRNA	miRNA Sponge	[76]
MnSOD	Melanomas	AluE	Mature mRNA	Secondary Structure Directly Impacting Translation	[63,64]
GLI1	Multiple Myeloma	AluY and AluSx	Mature mRNA	Inverted Repeat Alu RNA	[65]
TOMM40	Neurodegenerative Diseases	AluY	Intron	A-to-I Editing	97
SMN	Spinal Muscular Atrophy	AluY, AluSx1, and AluSq	Intron	Circular RNA	98
ATP7B	Wilson’s Disease	AluSq	Intron	Cryptic Exon Alternative Splicing	99

* – The mentioned human disease is only one example of those correlated with the given gene, and others not mentioned may exist. ** – Alu families were labelled as the original authors presented them or determined using the UCSC human genome browser (Kent et al., 100). If the Alu family could not be determined it was labelled as unclear in the table.

Figure 3. Schematic of an inverted repeat alu RNA. these structures arise when two different alu RNA sequences on a single pre-mRNA are transcribed anti-parallel to each other. due to their homology and orientation, these sequences can complementary base pair to form an inverted repeat. the formation of an inverted repeat alu RNA can also occur in a trans-acting mechanism, whereby alu RNA from two separate molecules interact to generate the double stranded structure [70]. inverted repeat alu RNA are targets for gene regulation as targets for STAU1 in mRNA decay, A-to-I editing by ADAR proteins, as well as precursors to back-splicing to allow for circular RNA formation [44,54,70]

Dewannieux M, Esnault C, Heidmann T. LINE-mediated retrotransposition of marked alu sequences. Nat Genet. 2003;35(1):41–48.

 PubMed Web of Science ®Google Scholar

Sorek R, Ast G, Graur D. Alu-containing exons are alternatively spliced. Genome Res. 2002;12(7):1060–1067.

 PubMed Web of Science ®Google Scholar

Walter P, Johnson AE. Signal sequence recognition and protein targeting. Annu Rev Cell Biol. 1994;10(1):87–119.

 PubMedGoogle Scholar

Häsler J, Strub K. Alu elements as regulators of gene expression. Nucleic Acids Res. 2006a;34(19):5491–5497.

 PubMed Web of Science ®Google Scholar

Häsler J, Strub K. Alu RNP and alu RNA regulate translation initiation in vitro. Nucleic Acids Res. 2006b;34(8):2374–2385.

 PubMed Web of Science ®Google Scholar

Knebelmann B, Forestier L, Drouot L, et al. Splice-mediated insertion of anAlu sequence in the COL4A3 mRNA causing autosomal recessive Alport syndrome. Hum Mol Genet. 1995;4(4):675–679.

 PubMed Web of Science ®Google Scholar

Nozu K, Iijima K, Ohysuka Y, et al. Alport syndrome caused by a COL4A5 deletion and exonization of an adjacent AluY. Mol Genet Genomic Med. 2014;2(5):451–453.

 PubMedGoogle Scholar

Pastor T, Talotti G, Lewandowska MA, et al. An Alu-derived intronic splicing enhancer facilitates intronic processing and modulates aberrant splicing in ATM. Nucleic Acids Res. 2009;37(21):7258–7267.

 PubMed Web of Science ®Google Scholar

Rome C, Loiseau H, Arsaut J, et al. Diversity of Contactin mRNA in Human Brain Tumors. Mol Carcinog. 2006;45(10):774–785.

 PubMed Web of Science ®Google Scholar

Paz N, Levanon EY, Amariglio N, et al. Altered adenosine-to-inosine RNA editing in human cancer. Genome Res. 2007;17(11):1586–1595.

 PubMed Web of Science ®Google Scholar

Booy EP, McRae EKS, Koul A, et al. The long non-coding RNA BC200 (BCYRN1) is critical for cancer cell survival and proliferation. Mol Cancer. 2017;16(1):109.

 PubMedGoogle Scholar

Booy EP, Gussakovsky D, Choi T, et al. The noncoding RNA BC200 associates with polysomes to positively regulate mRNA translation in tumor cells. J Biol Chem. 2021;296:100036.

 PubMed Web of Science ®Google Scholar

Stasenko M, Cybulska P, Feit N, et al. Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status. Gynecol Oncol. 2019;154(1):144–149.

 PubMed Web of Science ®Google Scholar

Thompson ME, Jensen RA, Obermiller PS, et al. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet. 1995;9(4):444–450.

 PubMed Web of Science ®Google Scholar

Sobczak K, Krzyzosiak WJ. Structural determinants of BRCA1 translational regulation. J Biol Chem. 2002;277(19):17349–17358.

 PubMed Web of Science ®Google Scholar

Haupt S, Vijayakumaran R, Miranda PJ, et al. The role of MDM2 and MDM4 in breast cancer development and prevention. J Mol Cell Biol. 2017;9(1):53–61.

 PubMed Web of Science ®Google Scholar

Chen LL, Yang L. ALUternative regulation for gene expression. Trends Cell Biol. 2017;27(7):480–490.

 PubMed Web of Science ®Google Scholar

Hoffman Y, Bublik DR, Pilpel Y, et al. miR-661 downregulates both Mdm2 and Mdm4 to activate p53. Cell Death Differ. 2014;21(2):302–309.

 PubMed Web of Science ®Google Scholar

Schollen E, Keldermans L, Foulquier F, et al. Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. Mol Genet Metab. 2007;90(4):408–413.

 PubMed Web of Science ®Google Scholar

Ferlini A, Galié N, Merlini L, et al. A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy. Am J Hum Genet. 1998;63(2):436–446.

 PubMed Web of Science ®Google Scholar

Shen S, Lin L, Cai JJ, et al. Widespread establishment and regulatory impact of Alu exons in human genes. Proc Natl Acad Sci U S A. 2011;108(7):2837–2842.

 PubMed Web of Science ®Google Scholar

Liang D, Wilusz JE. Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 2014;28(20):2233–2247.

 PubMed Web of Science ®Google Scholar

Hu D, Zhang Y. Circular RNA HIPK3 promotes glioma progression by binding to miR-124-3p. Gene. 2019;690:81–89.

 PubMed Web of Science ®Google Scholar

Yang C, Zheng J, Liu X, et al. Role of ANKHD1/LINC00346/ZNF655 Feedback Loop in Regulating the Glioma Angiogenesis via Staufen1-Mediated mRNA Decay. Mol Ther Nucleic Acids. 2020;20:866–878.

 PubMedGoogle Scholar

Mitchell GA, Labuda D, Fontaine G, et al. Splice-mediated insertion of an Alu sequence inactivates ornithine aminotransferase: A role for Alu elements in human mutation. Proc Natl Acad Sci U S A. 1991;88(3):815–819.

 PubMed Web of Science ®Google Scholar

Jourdy Y, Janin A, Fretigny M, et al. Reccurrent F8 intronic deletion found in mild hemophilia a causes alu exonization. Am J Hum Genet. 2018;102(2):199–206.

 PubMed Web of Science ®Google Scholar

Tan S, Li H, Zhang W, et al. NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. Oncogene. 2018;37(35):4887–4900.

 PubMed Web of Science ®Google Scholar

Capshew CR, Dusenbury KL, Hundley HA. Inverted alu dsRNA structures do not affect localization but can alter translation efficiency of human mRNAs independent of RNA editing. Nucleic Acids Res. 2012;40(17):8637–8645.

 PubMed Web of Science ®Google Scholar

Tomuschat C, O'Donnell AM, Coyle D, et al. NOS-interacting protein (NOSIP) is increased in the colon of patients with Hirschsprungs's disease. J Pediatr Surg. 2017;52(5):772–777.

 PubMed Web of Science ®Google Scholar

Brasil S, Viecelli HM, Meili D, et al. Pseudoexon exclusion by antisense therapy in 6-pyruvoyl-tetrahydropterin synthase deficiency. Hum Mutat. 2011;32(9):1019–1027.

 PubMed Web of Science ®Google Scholar

Bonnefoy S, Watson CM, Kernohan KD, et al. Biallelic Mutations in LRRC56, Encoding a Protein Associated with Intraflagellar Transport, Cause Mucociliary Clearance and Laterality Defects. Am J Hum Genet. 2018;103(5):727–739.

 PubMed Web of Science ®Google Scholar

Kim JS, Chang JW, Park JK, et al. Increased aldehyde reductase expression mediates acquired radioresistance of laryngeal cancer cells via modulating p53. Cancer Biol Ther. 2012;13(8):638–646.

 PubMed Web of Science ®Google Scholar

Saraei R, Soleimani M, Akbari AAM, et al. The role of XIAP in resistance to TNF-related apoptosis-inducing ligand (TRAIL) in Leukemia. Biomed Pharmacother. 2018;107:1010–1019.

 PubMed Web of Science ®Google Scholar

Hiraide T, Nakashima M, Ikeda T, et al. Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy. J Hum Genet. 2020;65(10):921–925.

 PubMed Web of Science ®Google Scholar

Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3ʹ UTRs via alu elements. Nature. 2011;470(7333):284–290.

 PubMed Web of Science ®Google Scholar

Bortolin-Cavaille ML, Dance M, Weber M, et al. C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts. Nucleic Acids Res. 2009;37(10):3464–3473.

 PubMed Web of Science ®Google Scholar

Zhang Y, Sun M, Chen Y, et al. MiR-519b-3p inhibits the proliferation and invasion in colorectal cancer via modulating the uMtCK/Wnt signaling pathway. Front Pharmacol. 2019b;10:1–9.

 PubMed Web of Science ®Google Scholar

Bhattacharya A, Jha V, Singhal K, et al. Multiple Alu exonization in 3ʹUTR of a primate specific isoform of CYP20A1 creates a potential miRNA sponge. Genome Biol Evol. 2021;13:evaa233.

 PubMed Web of Science ®Google Scholar

Oberley LW. Mechanism of the tumor suppressive effect of MnSOD overexpression. Biomed Pharmacother. 2005;59(4):143–148.

 PubMed Web of Science ®Google Scholar

Stuart JJ, Egry LA, Wong GH, et al. The 3ʹ UTR of human MnSOD mRNA hybridizes to a small cytoplasmic RNA and inhibits gene expression. Biochem Biophys Res Commun. 2000;274(3):641–648.

 PubMed Web of Science ®Google Scholar

Lazzari E, Mondala PK, Santos ND, et al. Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nat Commun. 2017;8(1):1922.

 PubMedGoogle Scholar

Larsen PA, Lutz MW, Hunnicutt KE, et al. The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease. Alzheimers Dement. 2017;13(7):828–838.

 PubMed Web of Science ®Google Scholar

Pagliarini V, Jolly A, Bielli P, et al. Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization. Nucleic Acids Res. 2020;48(2):633–645

 PubMed Web of Science ®Google Scholar

Mameli E, Lepori MB, Chiappe F, et al. Wilson's disease caused by alternative splicing and Alu exonization due to a homozygous 3039-bp deletion spanning from intron 1 to exon 2 of the ATP7B gene. Gene. 2015;569(2):276–279

 PubMed Web of Science ®Google Scholar

Kent WJ, Sugnet CW, Furey TS, et al. The Human Genome Browser at UCSC. Genome Res. 2002;12(6):996–1006.

 PubMed Web of Science ®Google Scholar

Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol. 2016;17(2):83–96.

 PubMed Web of Science ®Google Scholar