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Long and short non-coding RNA and radiation response: a review

2021; Elsevier BV; Volume: 233; Linguagem: Inglês

10.1016/j.trsl.2021.02.005

1931-5244

Jared M. May, Michelle A. Bylicky, Sunita Chopra, C. Norman Coleman, Molykutty J. Aryankalayil,

MicroRNA in disease regulation

Once thought of as arising from "junk DNA," noncoding RNAs (ncRNAs) have emerged as key molecules in cellular processes and response to stress. From diseases such as cancer, coronary artery disease, and diabetes to the effects of ionizing radiation (IR), ncRNAs play important roles in disease progression and as biomarkers of damage. Noncoding RNAs regulate cellular processes by competitively binding DNA, mRNA, proteins, and other ncRNAs. Through these interactions, specific ncRNAs can modulate the radiosensitivity of cells and serve as diagnostic and prognostic biomarkers of radiation damage, whether from incidental exposure in radiotherapy or in accidental exposure scenarios. Analysis of RNA expression after radiation exposure has shown alterations not only in mRNAs, but also in ncRNAs (primarily miRNA, circRNA, and lncRNA), implying an important role in cellular stress response. Due to their abundance and stability in serum and other biofluids, ncRNAs also have great potential as minimally invasive biomarkers with advantages over current biodosimetry methods. Several studies have examined changes in ncRNA expression profiles in response to IR and other forms of oxidative stress. Furthermore, some studies have reported modulation of radiosensitivity by altering expression levels of these ncRNAs. This review discusses the roles of ncRNAs in the radiation response and evaluates prior research on ncRNAs as biomarkers of radiation damage. Future directions and applications of ncRNAs in radiation research are introduced, including the potential for a clinical ncRNA assay for assessing radiation damage and for the therapeutic use of RNA interference (RNAi). Once thought of as arising from "junk DNA," noncoding RNAs (ncRNAs) have emerged as key molecules in cellular processes and response to stress. From diseases such as cancer, coronary artery disease, and diabetes to the effects of ionizing radiation (IR), ncRNAs play important roles in disease progression and as biomarkers of damage. Noncoding RNAs regulate cellular processes by competitively binding DNA, mRNA, proteins, and other ncRNAs. Through these interactions, specific ncRNAs can modulate the radiosensitivity of cells and serve as diagnostic and prognostic biomarkers of radiation damage, whether from incidental exposure in radiotherapy or in accidental exposure scenarios. Analysis of RNA expression after radiation exposure has shown alterations not only in mRNAs, but also in ncRNAs (primarily miRNA, circRNA, and lncRNA), implying an important role in cellular stress response. Due to their abundance and stability in serum and other biofluids, ncRNAs also have great potential as minimally invasive biomarkers with advantages over current biodosimetry methods. Several studies have examined changes in ncRNA expression profiles in response to IR and other forms of oxidative stress. Furthermore, some studies have reported modulation of radiosensitivity by altering expression levels of these ncRNAs. This review discusses the roles of ncRNAs in the radiation response and evaluates prior research on ncRNAs as biomarkers of radiation damage. Future directions and applications of ncRNAs in radiation research are introduced, including the potential for a clinical ncRNA assay for assessing radiation damage and for the therapeutic use of RNA interference (RNAi). IntroductionRadiation injury, either due to radiation therapy or a mass casualty radiation disaster, will affect multiple cellular pathways and produce heterogeneous effects across the population. In the instance of radiation therapy, the goal of biodosimetry is to aid in prognosis and early treatment of normal tissue damage. In a mass casualty scenario, biodosimetry will allow for rapid triaging of patients to distinguish the injured from the 'worried well' and to utilize limited resources most effectively. Biodosimetry was born from the recognition that the physical dose of radiation may differ from the extent of biological perturbations and examines chromosomal, metabolomic, proteomic, molecular and other physiological changes.1Coleman C.N. Koerner J.F. Biodosimetry: medicine, science, and systems to support the medical decision-maker following a large scale nuclear or radiation incident.Radiat Prot Dosimetry. 2016; 172: 38-46Crossref PubMed Scopus (21) Google Scholar Additionally, biodosimetry can be more quantifiable and verifiable than evaluation of clinical symptoms, which can have ranges in severity and onset.2Flood A.B. Nicolalde R.J Demidenko E et al.A framework for comparative evaluation of dosimetric methods to triage a large population following a radiological event.Radiat Meas. 2011; 46: 916-922Crossref PubMed Scopus (38) Google Scholar Sproull and Camphausen recognized 7 fields of biodosimetry: cytogenics, electron paramagnetic resonance, proteomics, metabolomics, genomics, lymphocyte kinetics, and transcriptomics, among which transcriptomics are the least studied.3Sproull M. Camphausen K. State-of-the-art advances in radiation biodosimetry for mass casualty events involving radiation exposure.Radiat Res. 2016; 186: 423-435Crossref PubMed Scopus (28) Google Scholar RNA biodosimetry markers offer several advantages over the current gold standard dicentric chromosome assay (DCA). The DCA method is limited by the reliance on culturing lymphocytes ex vivo, which requires several days to obtain a result and is labor intensive.4Fenech M. Current status, new frontiers and challenges in radiation biodosimetry using cytogenetic, transcriptomic and proteomic technologies.Radiation Measurements. 2011; 46: 737-741Crossref Scopus (25) Google Scholar Thus, in a mass casualty scenario, only a fraction of the population could be tested. The delay in results may also decrease the efficacy of early medical countermeasures. Additionally, the DCA method requires the presence of sufficient lymphocytes in the blood, so patients exposed to very high doses (>10 Gy) and without actively dividing cells would be precluded.4Fenech M. Current status, new frontiers and challenges in radiation biodosimetry using cytogenetic, transcriptomic and proteomic technologies.Radiation Measurements. 2011; 46: 737-741Crossref Scopus (25) Google Scholar Stable from degradation, readily abundant in bodily fluids and assayable via RT-PCR, ncRNAs could significantly shorten the time required for results over a cultured lymphocyte assay.This review will briefly describe characteristics of noncoding RNA and the physiological and biological effects of radiation damage, followed by specific ncRNAs involved in radiation response and examples of ncRNA biomarkers. Future directions for the field, including druggable RNA targets, considerations for bringing RNA biomarkers to practice, and organ-specific RNA markers will be addressed.Characteristics of ncRNAsThe completion of the ENCyclopedia of DNA Elements (ENCODE) project and the rapid advances in RNA-sequencing technology have revealed that 70% of the human genome is transcribed into RNA, with approximately 2.5% of that fraction translated into proteins through messenger RNA (mRNA).5Pennisi E. ENCODE project writes eulogy for junk DNA.Science. 2012; 337: 1159-1161Crossref PubMed Scopus (321) Google Scholar These revelations have drawn attention to the vast amount of noncoding RNA (ncRNA) and led to efforts to ascertain their functions. It is now readily apparent that ncRNAs, including micro RNA (miRNA), piwi-interacting RNA (piRNA), long noncoding RNA (lncRNA), transfer RNA (tRNA), circular RNA (circRNA), small nucleolar RNA (snoRNA), and small nuclear RNA (snRNA), have important roles in mRNA processing, chromatin remodeling, gene silencing, protein synthesis, and transcriptional and translational regulation. The primary and most studied ncRNAs implicated in radiation research are lncRNA, miRNA, and circRNA; thus, this review focuses on the contributions of these three classes of RNA to the radiation response and their roles as diagnostic and prognostic biomarkers and therapeutic targets.Long ncRNAs are characterized by transcript lengths of >200 nucleotides and lack of a clear protein coding region,6Uchida S. Dimmeler S. Long noncoding RNAs in cardiovascular diseases.Circ Res. 2015; 116: 737-750Crossref PubMed Scopus (452) Google Scholar though recent studies indicate a limited potential to code for micropeptides in select lncRNAs.7Yeasmin F. Yada T. Akimitsu N. Micropeptides encoded in transcripts previously identified as long noncoding RNAs: a new chapter in transcriptomics and proteomics.Front Genet. 2018; 9: 144Crossref PubMed Scopus (51) Google Scholar With approximately twice as many lncRNAs as protein-coding genes in human and mouse genomes, many functions of lncRNA are not yet well understood.6Uchida S. Dimmeler S. Long noncoding RNAs in cardiovascular diseases.Circ Res. 2015; 116: 737-750Crossref PubMed Scopus (452) Google Scholar Although more tissue-specific than mRNA, Derrien et al reported that 11% of lncRNAs are detected in all tissue types analyzed.8Derrien T. Johnson R Bussotti G et al.The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression.Genome Res. 2012; 22: 1775-1789Crossref PubMed Scopus (3237) Google Scholar They also reported a generally lower expression level of lncRNAs compared to mRNAs. Cellular processes are influenced by lncRNAs through 4 main methods: imprinting, scaffolding for epigenetic and transcription factors, enhancer activation, and as molecular sponges.6Uchida S. Dimmeler S. Long noncoding RNAs in cardiovascular diseases.Circ Res. 2015; 116: 737-750Crossref PubMed Scopus (452) Google Scholar,9Wang K.C. Chang H.Y. Molecular mechanisms of long noncoding RNAs.Mol Cell. 2011; 43: 904-914Abstract Full Text Full Text PDF PubMed Scopus (2839) Google Scholar Despite their vast roles, lncRNAs are poorly conserved between species by sequence.6Uchida S. Dimmeler S. Long noncoding RNAs in cardiovascular diseases.Circ Res. 2015; 116: 737-750Crossref PubMed Scopus (452) Google Scholar However, lncRNAs may also be conserved by secondary structure, allowing different sequences to exert the same functions.10Diederichs S. The four dimensions of noncoding RNA conservation.Trends Genet. 2014; 30: 121-123Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar In circulation, lncRNAs have been reported in bodily fluids including serum, urine, saliva.11Pardini B. Sabo A.A. Birolo G. Calin G.A. Noncoding RNAs in extracellular fluids as cancer biomarkers: the new frontier of liquid biopsies.Cancers (Basel). 2019; 11: 1-52Crossref Scopus (49) Google Scholar Figure 1 illustrates some of the ways lncRNAs interact with DNA, mRNA, proteins, and other ncRNAs to influence cellular processes. The significant involvement of lncRNAs in the innate immune response is reviewed by Hadjicharalambous and Lindsay.12Hadjicharalambous M.R. Lindsay M.A. Long non-coding RNAs and the innate immune response.Noncoding RNA. 2019; 5PubMed Google ScholarMicroRNAs are small single-stranded RNA transcripts of 21–25 nucleotides in length produced from hairpin loop precursors.13Wahid F. Shehzad A. Khan T. Kim Y.Y. MicroRNAs: synthesis, mechanism, function, and recent clinical trials.Biochimica et Biophysica Acta (BBA) - Mol Cell Res. 2010; 1803: 1231-1243Crossref PubMed Scopus (0) Google Scholar The primary method of miRNA action is through competitive partial binding with the 3' UTR of the target mRNA to inhibit translation and/or lead to mRNA degradation.14O'Brien J. Hayder H. Zayed Y. Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation.Front Endocrinol. 2018; 9Crossref PubMed Scopus (991) Google Scholar By binding complementary sequences, miRNAs have also been reported to interact with the 5' UTR, coding sequences, and gene promoters.15Broughton J.P. Lovci M.T. Huang J.L. Yeo G.W. Pasquinelli A.E. Pairing beyond the seed supports microRNA targeting specificity.Mol Cell. 2016; 64: 320-333Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar New miRNAs continue to be discovered, however there are several cases where the transcripts are highly conserved across species.16Pasquinelli A.E. Reinhart B Slack F et al.Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA.Nature. 2000; 408: 86-89Crossref PubMed Scopus (1749) Google Scholar, 17Davis-Dusenbery B.N. Hata A. Mechanisms of control of microRNA biogenesis.J Biochem. 2010; 148: 381-392PubMed Google Scholar, 18Li S.C. Chan W. Hu L.Y et al.Identification of homologous microRNAs in 56 animal genomes.Genomics. 2010; 96: 1-9Crossref PubMed Scopus (79) Google Scholar, 19Friedlander M.R. Lizano E Houben A et al.Evidence for the biogenesis of more than 1,000 novel human microRNAs.Genome Biol. 2014; : 15Google Scholar Specific to tissue and function the regulation of cellular processes by miRNA depends on the subcellular localization and the relative abundance of the miRNA and its target.20Ludwig N. Leidinger P Becker K et al.Distribution of miRNA expression across human tissues.Nucleic Acids Res. 2016; 44: 3865-3877Crossref PubMed Scopus (478) Google Scholar Additionally, miRNAs can be secreted into extracellular fluid and transported via exosomes or binding with proteins.14O'Brien J. Hayder H. Zayed Y. Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation.Front Endocrinol. 2018; 9Crossref PubMed Scopus (991) Google Scholar Previous studies have found detectable levels of miRNAs in serum, plasma, and urine and they are stable against degradation due to their small size and protection by exosomes.21Valadi H. Eckstrom K Bossios A et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.Nat Cell Biol. 2007; 9: 654-659Crossref PubMed Scopus (7770) Google Scholar,22Hunter M.P. Ismail N Zhang X et al.Detection of microRNA expression in human peripheral blood microvesicles.PLoS One. 2008; 3: e3694Crossref PubMed Scopus (1143) Google Scholar In addition to showing the actions of lncRNA, Figure 1 also highlights how miRNAs may bind mRNA to modulate translation.Unlike typical linear RNA, circRNA is a covalently closed loop and lacks both a 5' cap and 3' poly A tail.23Geng Y. Jiang J. Wu C. Function and clinical significance of circRNAs in solid tumors.J Hematol Oncol. 2018; 11: 98Crossref PubMed Scopus (120) Google Scholar Geng et al recognized five main characteristics of circRNA: abundance in eukaryotic organisms, stability due to the covalently closed loop structure that is protected from exonucleases, high conservation between species, primary cytoplasmic localization, and high tissue-specificity.23Geng Y. Jiang J. Wu C. Function and clinical significance of circRNAs in solid tumors.J Hematol Oncol. 2018; 11: 98Crossref PubMed Scopus (120) Google Scholar There are five categories of circRNAs: exonic, intronic, antisense, intragenic, and intergenic.24Rong D. Sun H Li Z et al.An emerging function of circRNA-miRNAs-mRNA axis in human diseases.Oncotarget. 2017; 8: 73271-73281Crossref PubMed Google Scholar Cellular processes can be modulated by circRNA through sequestering miRNA, regulating transcription by binding RNA Polymerase II, competing with linear splicing, and in select cases, by being translated into peptides.24Rong D. Sun H Li Z et al.An emerging function of circRNA-miRNAs-mRNA axis in human diseases.Oncotarget. 2017; 8: 73271-73281Crossref PubMed Google Scholar It is unclear if circRNA retains its function when not circularized. With approximately a 2.5-fold longer half-life than linear RNA, circRNA are resistant to exonuclease degradation and abundant in urine, plasma, saliva and gastric fluid.25Fang J. Qi J. Dong X. Luo J. Perspectives on circular RNAs as prostate cancer biomarkers.Front Cell Dev Biol. 2020; 8594992Crossref PubMed Scopus (0) Google ScholarPathophysiology of radiation damageEarly determination of the extent of radiation injury through ncRNA biomarker detection could provide a means to treat this damage early and potentially prevent late radiation-induced disease. Radiation induces direct and indirect damage, with radiation-induced double strand breaks considered the most lethal.26Ward J.F. The yield of DNA double-strand breaks produced intracellularly by ionizing radiation: a review.Int J Radiat Biol. 1990; 57: 1141-1150Crossref PubMed Scopus (265) Google Scholar Direct damage results from deposition of energy directly onto DNA molecules, whereas indirect damage stems from deposition of energy in other molecules, which then react with DNA.27Alizadeh E. Sanz A.G. Garcia G. Sanche L. Radiation damage to DNA: the indirect effect of low energy electrons.J Phys Chem Lett. 2013; 4: 820-825Crossref PubMed Scopus (62) Google Scholar The 4 steps of radiation damage to intracellular molecules are as follows: (1) Physical deposition of energy, (2) Generation of primary radicals in the target molecules, (3) Reaction of primary radicals on adjacent molecules, and (4) Production of chemically stable damage by unstable radicals.26Ward J.F. The yield of DNA double-strand breaks produced intracellularly by ionizing radiation: a review.Int J Radiat Biol. 1990; 57: 1141-1150Crossref PubMed Scopus (265) Google Scholar Additionally, mitochondria that are irradiated produce reactive oxygen species (ROS), another driver of DNA damage.28Li M. You L. Xue J. Lu Y. Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: a mini review.Front Pharmacol. 2018; 9: 522Crossref PubMed Scopus (49) Google Scholar Historically, hydroxyl radicals have been considered the key species in DNA damage, however recent research has determined the key species is a carbonate radical anion formed in the Fenton reaction.29Fleming A.M. Burrows C.J. On the irrelevancy of hydroxyl radical to DNA damage from oxidative stress and implications for epigenetics.Chem Soc Revi. 2020; 49: 6524-6528Crossref PubMed Google Scholar This carbonate radical anion is more abundant at physiological conditions than the hydroxyl radical and generates 8-oxo-7,8-dihydroguanine at GGG sites in DNA, which signals for DNA repair to begin.29Fleming A.M. Burrows C.J. On the irrelevancy of hydroxyl radical to DNA damage from oxidative stress and implications for epigenetics.Chem Soc Revi. 2020; 49: 6524-6528Crossref PubMed Google ScholarEffects of radiation are a function of dose with a threshold, above which injury is imminent and below which most people, cells, tissues, or animals experience little to no acute effects.30Mathes S.J. Alexander J. Radiation injury.Surg Oncol Clin N Am. 1996; 5: 809-824Abstract Full Text PDF PubMed Google Scholar Radiation response is also determined by type of radiation source, volume of tissue irradiated, and time after irradiation. A cell's specific radiosensitivity is in part determined by DNA replication, recombination, and repair.31Willers H. Dahm-Daphi J. Powell S.N. Repair of radiation damage to DNA.Br J Cancer. 2004; 90: 1297-1301Crossref PubMed Scopus (96) Google Scholar Double strand breaks are repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ).31Willers H. Dahm-Daphi J. Powell S.N. Repair of radiation damage to DNA.Br J Cancer. 2004; 90: 1297-1301Crossref PubMed Scopus (96) Google Scholar DNA damage response to double strand breaks includes protein recruitment, modifications such as histone phosphorylation, and activation of signaling pathways such as p53-p21.28Li M. You L. Xue J. Lu Y. Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: a mini review.Front Pharmacol. 2018; 9: 522Crossref PubMed Scopus (49) Google Scholar The role of noncoding RNAs in DNA damage repair have been thoroughly reviewed by Thapar.32Thapar R. Regulation of DNA double-strand break repair by non-coding RNAs.Molecules. 2018; : 23Google Scholar Ionizing radiation can also induce senescence in normal cells, resulting in persistent cell cycle arrest or mutation leading to cancer or cell death.28Li M. You L. Xue J. Lu Y. Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: a mini review.Front Pharmacol. 2018; 9: 522Crossref PubMed Scopus (49) Google ScholarSeverity of systemic effects depends on the volume of the body irradiated, exposure of critical organs, and dose received. In humans, whole body doses over 2 Gy can yield clinical symptoms of acute radiation syndrome, though symptoms, severity, and onset vary in populations.33DiCarlo A.L. Maher C Hick J.L et al.Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation.Disaster Med Public Health Prep. 2011; 5: S32-S44Crossref PubMed Scopus (141) Google Scholar Organ systems dependent on continuous cell turnover like the hematopoietic, pulmonary and gastrointestinal systems are affected sooner and more severely since they depend on frequent cell-divisions from stem cells and/or mucous membranes with rapid turnover of epithelial cells, which are destroyed by radiation.34Shadad A.K. Sullivan F.J. Martin J.D. Egan L.J. Gastrointestinal radiation injury: symptoms, risk factors and mechanisms.World J Gastroenterol. 2013; 19: 185-198Crossref PubMed Google Scholar,35Gruber S. Dorr W. Tissue reactions to ionizing radiation-oral mucosa.Mutat Res. 2016; 770: 292-298Crossref PubMed Scopus (16) Google Scholar Systems with terminally differentiated cells like cardiovascular and nervous systems exhibit fewer acute effects unless damage is supralethal.36Waselenko J.K. MacVittie T.J Blakely W.F et al.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.Annals of Internal Medicine. 2004; 140: 1037-1051Crossref PubMed Google ScholarAcute effects on the skin are largely erythema but may also include destruction of sebaceous glands, hair loss, and hyperpigmentation at higher doses. Chronic effects on skin and mucosa include fibrosis and decreased vascularity.30Mathes S.J. Alexander J. Radiation injury.Surg Oncol Clin N Am. 1996; 5: 809-824Abstract Full Text PDF PubMed Google Scholar In the musculoskeletal system, radiation may cause hypoplasia of facial bones in children, whereas adult bones are much more resistant. Interestingly, necrosis of muscle requires extreme doses exceeding 500 Gy.30Mathes S.J. Alexander J. Radiation injury.Surg Oncol Clin N Am. 1996; 5: 809-824Abstract Full Text PDF PubMed Google Scholar In the gastrointestinal system, radiation results in the breakdown of the mucosal layer, which may present clinically as abdominal pain, diarrhea, vomiting, and malnutrition.36Waselenko J.K. MacVittie T.J Blakely W.F et al.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.Annals of Internal Medicine. 2004; 140: 1037-1051Crossref PubMed Google Scholar The hematopoietic system suffers significantly from whole or partial body irradiation, with widespread cell death occurring in bone marrow progenitors exposed.36Waselenko J.K. MacVittie T.J Blakely W.F et al.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.Annals of Internal Medicine. 2004; 140: 1037-1051Crossref PubMed Google Scholar Irradiation also leads to lymphocyte depletion within the first 48 hours, resulting in alterations of whole blood RNA expression patterns.36Waselenko J.K. MacVittie T.J Blakely W.F et al.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.Annals of Internal Medicine. 2004; 140: 1037-1051Crossref PubMed Google Scholar From studies on radiotherapy patients treated for thoracic tumors, it is known that radiation induces acute pneumonitis and chronic pulmonary fibrosis in the late stage.37Kasmann L. Dietrich A Staab-Weijnitz C.A et al.Radiation-induced lung toxicity - cellular and molecular mechanisms of pathogenesis, management, and literature review.Radiat Oncol. 2020; 15: 214Crossref PubMed Scopus (1) Google Scholar In the cardiovascular system, radiation can induce pericardial disease, fibrosis, coronary artery disease (CAD), valvular injury and cardiac conduction system injury.38Liu L.K. Ouyang W Zhao X et al.Pathogenesis and prevention of radiation-induced myocardial fibrosis.Asian Pac J Cancer Prev. 2017; 18: 583-587PubMed Google Scholar Chronically, the accumulation of genetic abnormalities from radiation-induced DNA damage can result in the development of leukemia approximately 10 years after exposure or other solid tumors up to 30 years after exposure.39Prasad K.N. Cole W.C. Hasse G.M. Health risks of low dose ionizing radiation in humans: a review.Exp Biol Med (Maywood). 2004; 229: 378-382Crossref PubMed Google ScholarOf immediate concern is the development of acute radiation syndrome, which encompasses the damage to the hematopoietic, gastrointestinal, and cerebrovascular, and cutaneous symptoms that appear shortly after exposure.36Waselenko J.K. MacVittie T.J Blakely W.F et al.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.Annals of Internal Medicine. 2004; 140: 1037-1051Crossref PubMed Google Scholar Although analysis of clinical symptoms may provide some information on dose of radiation received, symptoms may not manifest for several days or weeks after exposure and have a range of severity, complicated by the possibility of psychological impacts.36Waselenko J.K. MacVittie T.J Blakely W.F et al.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.Annals of Internal Medicine. 2004; 140: 1037-1051Crossref PubMed Google Scholar Development of ncRNAs as a biomarker could potentially allow clinicians to determine preventative measures to treat radiation damage in both cancer patients and civilians exposed to radiation, mitigating symptoms such as nausea, vomiting, diarrhea, fibrosis, and anemia. Early intervention may also confer a survival advantage.36Waselenko J.K. MacVittie T.J Blakely W.F et al.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.Annals of Internal Medicine. 2004; 140: 1037-1051Crossref PubMed Google ScholarncRNAs in radiation responseWith widespread roles in disease progression and as biomarkers for disease, efforts began to focus on the role of ncRNAs in radiation response. Specifically, many studies were undertaken to discern how ncRNAs can modulate the radiosensitivity in normal and cancerous tissues in vitro. Although certain chemotherapeutics differentially modulate radiosensitivity of healthy versus cancerous cells,40Weigert V. Jost T Hecht M et al.PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts.BMC Cancer. 2020; 20: 775Crossref PubMed Scopus (2) Google Scholar ncRNAs may have the same effect but further research is needed. Several examples of ncRNAs involved with radiation response are given in Table 1, Table 2, Table 3. Additionally, it is now clear that cells respond differentially to single-dose and multi-fraction radiation providing unique opportunities for radiation combined with molecular therapeutics.41Coleman C.N. Eke I Makinde A.Y et al.Radiation-induced adaptive response: new potential for cancer treatment.Clinical Cancer Research. 2020; 26: 1-10Crossref PubMed Scopus (1) Google Scholar This section presents ncRNAs which have been shown to impact radiosensitivity of cells.Table 1Roles of specific lncRNAs in the regulation of radiosensitivity and radioresistance. The specific lncRNA, target molecule, model, and its role in radiation response are described. Italics = lncRNA whose expression increases radioresistance; underlined = lncRNA whose expression increases radiosensitivity. Open table in a new tab Table 2Roles of specific miRNAs in the regulation of radiosensitivity and radioresistance. The specific miRNA, target molecule, model, and its role in radiation response are described. Italics = miRNA whose expression increases radioresistance; underlined = miRNA whose expression increases radiosensitivity. Open table in a new tab Table 3Roles of specific circRNAs in the regulation of radiosensitivity and radioresistance. The specific lncRNA, target molecule, model, and its role in radiation response are described. Italics = circRNA whose expression increases radioresistance. Open table in a new tab lncRNAs in radiation responseTable 1 highlights several lncRNAs that affect radiation response in a variety of tissue models, as well as the targets of the lncRNA and mechanism of action. Figure 2 illustrates the action and the effects of three lncRNAs, HOTAIR, TUG1, and GAS5, which have multiple targets described in the literature. In breast cancer models, the lncRNA HOTAIR has been shown to increase radioresistance through targeting of miR-218 and miR-449b-5p.42Hu X. Ding D. Zhang J. Cui J. Knockdown of lncRNA HOTAIR sensitizes breast cancer cells to ionizing radiation through activating miR-218.Biosci Rep. 2019; 39: 1-9Crossref Scopus (25) Google Scholar,43Zhang S. LncRNA HOTAIR enhances breast cancer radioresistance through facilitating HSPA1A expression via sequestering miR-449b-5p.Thorac Cancer. 2020; 11: 1801-1816Crossref PubMed Scopus (2) Google Scholar Hu et al showed that HOTAIR is upregulated in breast cancer cell lines over normal tissue and increases in expression after 8 Gy irradiation. Furthermore, they reported