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Review
. 2024 Aug 8;11(1):53.
doi: 10.1186/s40779-024-00553-4.

Advances in the mechanism of small nucleolar RNA and its role in DNA damage response

Li-Ping Shen #  1 , Wen-Cheng Zhang #  1 , Jia-Rong Deng #  2 , Zhen-Hua Qi  1 , Zhong-Wu Lin  1 , Zhi-Dong Wang  3   4
Affiliations
Review

Advances in the mechanism of small nucleolar RNA and its role in DNA damage response

Li-Ping Shen et al. Mil Med Res. .

Abstract

Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.

Keywords: Cell cycle checkpoints; Cell death; DNA damage repair; DNA damage response (DDR); Oxidative stress; Small nucleolar RNAs (snoRNAs).

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Conflict of interest statement

All authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Synthetic mechanism and classification of small nucleolar RNAs (snoRNAs). a Biosynthesis of snoRNAs. b Schematic diagram of snoRNA structure and classification. Sno snoRNA, Exo exons, NΨ nucleotides modified by psuedouridylation, CAB small Cajal body localization element
Fig. 2
Fig. 2
Mechanisms through which small nucleolar RNAs (snoRNAs) interact with targets. a snoRNAs facilitate the post-transcriptional modifications of certain RNA molecules. b snoRNA-mediated alternative splicing by adjusting the activity of spliceosome or RNA editing. c snoRNA-derived small RNA fragments (sdRNAs) mediate gene silencing, functioning as miRNAs or piRNAs. d Involvement of snoRNAs during the pre-mRNA processing, with SNORD50A as an example. SNORD50A directly interacts with Fip1, a core component of cleavage and polyadenylation specificity factor (CPSF) at the poly(A) site to maintain moderate mRNA 3’ processing efficiency, and SNORD50A knockdown leads to process disruption. e snoRNAs regulate post-translational modifications (PTMs) through RNA-protein interactions, leading to changes in the activity and stability of certain proteins. Eon exon, Int intron, rRNA ribosomal RNA, snRNA small nuclear RNA, tRNA transfer RNA, mRNA messenger RNA, miRNA microRNA, piRNA Piwi-interacting RNA, RISC RNA-induced silencing complex, A-I adenine to inosine
Fig. 3
Fig. 3
Primary process of DNA damage response (DDR). PIKK phosphatidylinositol 3-kinase-related kinase, MRN MRE11-RAD50-NBS1, PARP poly adenosine diphosphate (ADP)-ribose polymerases, KU KU70/KU86 (or KU80) heterodimer, RPA replication protein A, RAD17 radiation sensitive 17, MDC1 mediator of DNA damage checkpoint 1, 53BP1 p53-binding protein 1, γ-H2AX γ-H2A variant X, BRCA1 breast cancer susceptibility protein 1, TOPBP1 DNA topoisomerase II-binding protein 1, CHK checkpoint kinase, CDC cell division cyclin, NF-κB nuclear factor-κB, BER base excision repair, NER nucleotide excision repair, MMR mismatch repair, SSBR single-strand break repair, HR homologous recombination, NHEJ nonhomologous end joining, Alt-NHEJ alternative-NHEJ
Fig. 4
Fig. 4
Expression and localization of small nucleolar RNAs (snoRNAs) in response to oxidative stress. For example, rpL13a snoRNAs shuttle from the nucleolus to the cytoplasm during the oxidative stress response, depending on the function of NADPH oxidase. The translocation of these snoRNAs induces endoplasmic reticulum (ER) stress-associated cell death. Sno snoRNA, rpL13a ribosomal protein L13a, DPI diphenyleneiodonium chloride, MnT Mn (III)TMPyP, NADPH nicotinamide adenine dinucleotide phosphate, H2O2 hydrogen peroxide, ROS reactive oxygen species, RNASET2 ribonuclease T2
Fig. 5
Fig. 5
Small nucleolar RNAs (snoRNAs) regulation of PARP-1 expression and activity. C/D box SNORD104 enhances the stability of PARP-1 mRNA through 2’-O-methylation (2’-O-Me), thereby promoting the expression of PARP-1 protein. SNORA73 (human), SNORA37 (human), SNORA74 (human), snora64 (mouse), snora7a (mouse), and snord16a (mouse) are snoRNAs involved in PARP-1-mediated PARylation, exerting either positive or negative effects on cell differentiation and proliferation. SNORD box C/D small nucleolar RNA, PARP-1 poly adenosine diphosphate (ADP)-ribose polymerases-1, PARylation poly-ADP-ribosylation, AML acute myeloid leukemia, DKC1 dyskerin pseudouridine synthase synthase 1, NHP2 H/ACA ribonucleoprotein complex subunit 2, BC breast cancer, DDX21 DExD-box helicase 21, PAR poly(ADP-ribose), rDNA ribosomal DNA, NMNAT-1 nicotinamide mononucleotide adenylyltransferase-1
Fig. 6
Fig. 6
Small nucleolar RNAs (snoRNAs) regulation of the activity of DDR-related PIKKs. DNA-PKcs is phosphorylated at the Thr2609 site by U3 during hematopoiesis in mice. However, the involvement of U3-mediated activation of DNA-PKcs in DDR remains unknown. scaRNA2 appears as a negative regulator of DNA-PKcs activation. It binds to DNA-PKcs and weakens its interaction with KU70/80 subunits, thereby inhibiting the autophosphorylation of DNA-PKcs at the Ser2056 and Thr2609 sites. Meanwhile, scaRNA2 sequesters LINP1 to inhibit the activity of DNA-PKcs. The obstruction of DNA-PKcs activation induced by scaRNA2 prompts cells to opt for HR repair in DDR, and undoubtedly, the scaRNA2-mediated phosphorylation of ATR contributes to this process. U3 small nucleolar RNA U3, LINP1 lncRNA in nonhomologous end joining pathway 1, scaRNA small Cajal body-specific RNA, DNA-PKcs DNA-dependent protein kinase catalytic subunit, ATM ataxia telangiectasia mutated, MRN MRE11-RAD50-NBS1, XRCC4 X-ray repair cross-complementing protein 4, LIG4 DNA ligase 4, EXO1 exonuclease 1, ssDNA single-stranded DNA, ATR ATM and Rad3-related, RPA2 replication protein A2, BRCA1 breast cancer susceptibility protein 1, RAD51 radiation sensitive 51, HR homologous recombination, NHEJ nonhomologous end joining
Fig. 7
Fig. 7
Small nucleolar RNAs (snoRNAs) regulation of cell cycle checkpoints. The cyclin/CDK complex refers to cyclinD-CDK4/6, cyclinE/A-CDK2, or cyclinB1/CDK1. The G1/S checkpoint is primarily regulated by cyclinD-CDK4/6 and cyclinE/A-CDK2 complexes via the phosphatase CDC25-mediated dephosphorylation, thereby facilitating the G1/S transition. Meanwhile, p53 and p21 act as inhibitors during the transition, whereas the phosphorylated Rb acts as an activator. Several snoRNAs participate in G1/S transition by regulating the expression of p53, p21, and Rb, as depicted in the figure. Likewise, the cyclinB1/CDK1 complex, activated by CDC25, governs the activity of the G2/M checkpoint to mediate the transition from the G2 phase to the M phase. SNORD47 and SNORD52 are involved in G2/M transition by targeting either CDC25 or cyclinB1/CDK1. In addition, U50A acts as an inhibitor in mitosis. In DDR (e.g., ionizing radiation-induced DNA damage), CDC25 is inactivated by ATM-CHK2/ATR-CHK1-mediated phosphorylation, ultimately leading to the inactivation of CDKs and causing cell cycle arrest. The snoRNA-mediated regulation of the cell cycle in DDR remains unknown. SNORD box C/D small nucleolar RNA, SNORA box H/ACA small nucleolar RNA, MDM2 mouse double minute 2, E6 human papillomavirus oncoprotein E6, GMPS guanosine 5’-monophosphate synthase, CDC25 cell division cyclin, CDKs cyclin-dependent kinases, E2F E2 family, Rb retinoblastoma tumor suppressor protein, DDR DNA damage response, CHK checkpoint kinase, ATM ataxia telangiectasia mutated, ATR ATM and Rad3-related, Ub ubiquitination
Fig. 8
Fig. 8
A framework of snoRNA in mediating genomic stress-induced DDR. snoRNA small nucleolar RNAs, 2’-O-Me 2’-O-methylation, ψ pseudouridylation, Ace acetylation, mRNA messenger RNA, Exo exon, Int intron, PTM post-translational modification, DDR DNA damage response, G1 gap1 phase, S synthesis phase, G2 gap2 phase, M mitotic phase
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