Non-coding RNAs: an emerging player in DNA damage response.

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MUTREV-8099; No. of Pages 10 Mutation Research xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Mutation Research/Reviews in Mutation Research journal homepage: www.elsevier.com/locate/reviewsmr Community address: www.elsevier.com/locate/mutres

Review

Non-coding RNAs: An emerging player in DNA damage response Chunzhi Zhang a,*, Guang Peng b,** a b

Department of Radiation Oncology, Tianjin Huan Hu Hospital, Tianjin 300060, China Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, United States

A R T I C L E I N F O

A B S T R A C T

Article history: Received 30 August 2014 Received in revised form 3 November 2014 Accepted 4 November 2014 Available online xxx

Non-coding RNAs play a crucial role in maintaining genomic stability which is essential for cell survival and preventing tumorigenesis. Through an extensive crosstalk between non-coding RNAs and the canonical DNA damage response (DDR) signaling pathway, DDR-induced expression of non-coding RNAs can provide a regulatory mechanism to accurately control the expression of DNA damage responsive genes in a spatio-temporal manner. Mechanistically, DNA damage alters expression of a variety of noncoding RNAs at multiple levels including transcriptional regulation, post-transcriptional regulation, and RNA degradation. In parallel, non-coding RNAs can directly regulate cellular processes involved in DDR by altering expression of their targeting genes, with a particular emphasis on miRNAs and lncRNAs. MiRNAs are required for almost every aspect of cellular responses to DNA damage, including sensing DNA damage, transducing damage signals, repairing damaged DNA, activating cell cycle checkpoints, and inducing apoptosis. As for lncRNAs, they control transcription of DDR relevant gene by four different regulatory models, including signal, decoy, guide, and scaffold. In addition, we also highlight potential clinical applications of non-coding RNAs as biomarkers and therapeutic targets for anti-cancer treatments using DNA-damaging agents including radiation and chemotherapy. Although tremendous advances have been made to elucidate the role of non-coding RANs in genome maintenance, many key questions remain to be answered including mechanistically how non-coding RNA pathway and DNA damage response pathway is coordinated in response to genotoxic stress. ß 2014 Elsevier B.V. All rights reserved.

Keywords: DNA damage response Non-coding RNAs miRNAs lncRNAs

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DNA damage regulates the biogenesis of noncoding RNAs . . . . . . . . . . . . . . . . . . . . miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. DNA damage transcriptionally modulates miRNA expression . . . . . 2.1.1. DNA damage post-transcriptionally modulates miRNA expression. 2.1.2. DNA damage modulates miRNA degradation . . . . . . . . . . . . . . . . . . 2.1.3. LncRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Other noncoding RNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Non-coding RNAs regulate DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. miRNAs regulate DDR sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. miRNAs regulate DDR transducers . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. miRNAs regulate DDR effectors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. lncRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Signal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Decoy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Scaffold. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4.

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* Corresponding author at: Department of Radiation Oncology, Tianjin Huanhu Hospital, 122 Qixiangtai Road, Hexi District, Tianjin, 300060, China. Tel.: +86 022 60367691. ** Corresponding author at: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77054, United States. Tel.: +1 713 834 6151. E-mail addresses: [email protected] (C. Zhang), [email protected] (G. Peng). http://dx.doi.org/10.1016/j.mrrev.2014.11.003 1383-5742/ß 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: C. Zhang, G. Peng, Non-coding RNAs: An emerging player in DNA damage response, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.11.003

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3.3. Other non-coding RNAs . . . . . . . . . . . Potential clinical applications of non-coding Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Reliable transmission of genetic information from cells to daughter cells is essential for maintaining cells’ genomic stability and survival. However, cells are continuously challenged by DNA damage stimuli from various exogenous and endogenous sources, such as ultraviolet (UV) radiation, ionizing radiation (IR), numerous genotoxic chemicals, and the byproducts of cellular metabolism such as reactive oxidative species. To maintain genome integrity, eukaryotes have evolved an evolutionarily conserved DNA damage response (DDR) system [1]. DDR involves multiple well-coordinated processes that sense DNA damage, transduce DNA damage signals, promote DNA damage repair, activate cell cycle checkpoints, and induce apoptosis when damage is unrepairable [2]. DNA damage can lead to a variety of DNA lesions, such as base adducts, DNA mismatch, insertion/deletion, O6 alkyguanine, inter-strand DNA crosslinking, single-strand breaks, and doublestrand breaks (DSBs) [3]. Among all DNA lesions, DSBs have the most deleterious effects on cell survival. If DSBs are not repaired, cell death is induced by the persistence of DSBs. To maintain their genomic stability and survival, cells use two major pathways to repair DSBs: nonhomologous end-joining (NHEJ), which is an errorprone process predominantly in the G0/G1 cell-cycle phase, and homologous recombination repair (HRR), which is an error-free process predominantly in the late S/G2-phase [4]. Given the fundamental role of DDR in maintaining genome integrity, this complex signaling network requires accurate regulatory mechanisms to respond to different types of DNA lesions in different stages of the cell cycle. In the past decade, accumulating experimental evidence has shown that non-coding RNAs—including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), DNA damage response RNAs (DDRNAs), DSB-induced RNAs (diRNAs), small interfering RNA (siRNAs), and piwiinteracting RNAs (piRNAs)—are emerging new players in DDR [5]. DNA damage also induces alterations in the expression of these non-coding RNAs [6–9]. Based on the kinetics of DDR, noncoding RNA-associated molecular changes occur later than posttranslational protein modifications, such as phosphorylation, acetylation, and ubiquitination [10]. However, the non-coding RNA response occurs earlier than transcriptional regulation of gene expression. Presumably, non-coding RNA-regulated DDR connects with the fast phase of DDR mediated by protein translational modifications and the slow phase of DDR mediated by transcriptional gene expression programs (Fig. 1). Thus, noncoding RNAs provide a key node to link the various kinetic phases of DDR. Here, we discuss the characteristics and biological roles of these non-coding RNAs in DDR, with a special emphasis on miRNAs and lncRNAs. Based on our current knowledge, we propose molecular models underlying the functions of non-coding RNAs in DDR. Furthermore, we discuss potential clinical applications of non-coding RNAs as predictive biomarkers and therapeutic targets for anti-cancer treatments using DNA-damaging agents including radiation and chemotherapy.

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initiate cell cycle arrest, which allows time for DNA repair. At the same time, DDR activates the gene transcription program, which allows the expression of key genes involved in DNA repair and cell cycle regulation. Recent studies have shown that in addition to these protein-coding genes, a subset of non-coding RNAs is also required for cellular responses to DNA damage [11,12]. To coordinate non-coding RNA-mediated DDR, DNA damage can alter the expression levels of non-coding RNAs [6,13–15]. 2.1. miRNAs Several studies have shown that the expression profile of miRNAs is altered by DNA damage when cells were treated with different types of genotoxic agents, such as UV radiation, IR, oxidative stress, and chemical mutagenes [15–18]. A few hours after DNA damage, a subset of miRNAs is upregulated while another subset of miRNAs is downregulated. miRNA expression can return to the basal level 24 h after DNA damage. DNA damage induces alterations in miRNA expression at multiple levels including transcriptional regulation, post-transcriptional regulation, and degradation (Fig. 2). 2.1.1. DNA damage transcriptionally modulates miRNA expression At the transcriptional level, DNA damage can activate transcription factors, such as p53, c-myc, and c-jun, which play a classic role in regulating miRNA expression. For example, the tumor suppressor p53 is a key factor that is induced by DNA damage. One study showed that miRNA expression profiles are

2. DNA damage regulates the biogenesis of noncoding RNAs DDR has a broad impact on multiple cellular processes. To ensure efficient DNA repair, cell cycle checkpoints are activated to

Fig. 1. DNA damage-induced non-coding RNA response functions as a connectivity node between the rapid DNA damage response mediated by protein modifications and the late response mediated by transcriptional regulation.


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Fig. 2. DNA damage induces alteration of miRNAs profiles by transcriptional regulation, post-transcriptal regulation and degradation. At the transcriptional level, DNA damage can activate transcription factors, such as p53, c-myc, and c-jun, which play a classic role in regulating miRNA expression. At the post-transcriptional level, DNA damage can affect miRNA expression by regulating the essential steps of miRNA processing and maturation, such as Drosha, Xpo5, Dicer, miRNAs degradation can also be a potential regulatory step, which needs further investigation.

different between p53 wild-type cells and p53-deficient cells [19]. Among these differentially expressed miRNAs, the miR-34 family was the first identified transcriptional target of p53 [20]. Further studies showed that DNA damage induces the miR-34 family in a p53-dependent manner [21,22]. In addition to activating the miR-34 family, p53 can transcriptionally activate miR-15a/16, miR-29, miR-107, miR-145, miR-192, miR-194, miR215, and miR-605 and transcriptionally repress miR-17-92 [23–28]. By regulating their target genes, p53-induced miRNAs can modulate DDR and cell cycle progression. Notably, p53induced miRNAs can in turn activate and stabilize p53, and this process forms a regulatory loop between these miRNAs and p53 [21]. In addition to p53, many other DNA damage-responsive transcription factors such as nuclear factor-kappa B (NF-kB), E2F1, c-jun, and Myc are involved in modulating miRNA expression. For example, E2F1 and c-Myc activate the transcription of miR-1292 [29,30]; c-Myc increases miR-20a, miR-221, and miR-222 at the transcriptional level [31]; and NF-kB and c-jun promote gene transcription of miR-221 and miR-222 [32,33]. In addition to miR221 and miR-222, NF-kB alone transcriptionally regulates miR-21 [34]. In the future, global prediction and verification of promoter regions of miRNA genes will help us comprehensively understand the interplay between DNA damage-induced transcriptional factor and miRNA expression.

2.1.2. DNA damage post-transcriptionally modulates miRNA expression At the post-transcriptional level, DNA damage can affect miRNA expression by regulating the essential steps of miRNA processing and maturation. DNA damage induces robust activation of the phosphoinositide 3-kinase (PI3K)-like protein kinases ATM, ATR, and DNA-PKcs, which not only initiates the phosphorylation signaling cascade of DDR [35,36] but also plays a central role in regulating miRNA expression after DNA damage. Several studies have shown that DNA damage-induced miRNAs biogenesis can occur in an ATM-dependent manner [37]. ATM activation can phosphorylate KH-type splicing regulatory protein (KSRP), which is an interacting protein of the miRNA processing enzymes Drosha and Dicer. Through the recognition of the terminal loop region of primary miRNAs (pri-miRNAs), KSRP can regulate miRNA maturation in response to DNA damage, which leads to alterations in the expression of multiple miRNAs, including pri-miR-1, pri-miR-15, pri-miR-21, and pri-let-7 [37]. In addition to KSRP, BRCA1 is activated by ATM after DNA damage and can directly interact with Drosha, DEAD box RNA helicase p68 (DDX5), and pri-miRNAs to facilitate the processing of pri-miRNAs [38]. In line with this observation, ATM-activated p53 can directly interact with DDX5/ DEAD box RNA helicase p72 (DDX17) to promote pri-miRNA processing under DNA damage [39]. Furthermore, ATM also


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activates DNp63a, which transcriptionally modulates miRNA expression and upregulates Dicer to accelerate miRNA maturation after treatment with the DNA damage-inducing agent cisplatin [40]. In a recent study, Wan et al. [41] reported that ATM-activated AKT kinase phosphorylates Nup153, a key component of the nucleopore, resulting in enhanced interaction between Nup153 and Exportin-5 (XPO5) and increased nuclear export of precursor miRNAs (pre-miRNAs). Collectively, these studies demonstrate that DNA damage response can affect miRNA expression by regulating pre-miRNA maturation. The other two PI3K-like protein kinases, ATR and DNA-PKcs, have also been found to regulate miRNA expression after DNA damage. Chaudhry et al. [42] discovered that alterations in miRNA expression are different between DNA-PKcs-deficient glioma cells (M059J) and DNA-PKcs-proficient glioma cells. This result suggested that these altered miRNAs were modulated in a DNAPKcs-dependent manner. Another study reported that miR-709 is potentially induced in an ATR-dependent manner [43]. Drosha is known to interact with DGCR8 to form a complex called microprocessor, which plays a key role in regulating the homeostasis of miRNA biogenesis. A recent study showed that oxidative stressresponsive heme oxygenase-1 modulates miRNA expression by downregulating DGCR8 [44]. Moreover, IR activates the epidermal growth factor receptor/ERBB family of receptor tyrosine kinases, which activates the MAPK/Erk or PI3K/Akt pathway. As a consequence, MAPK/Erk signaling modulates stability of Ago2 and DicerTRBP complex to affect miRNA maturation [45]. Akt signaling and epidermal growth factor receptor can also phosphorylate Ago2 to change the miRNA expression profile [46,47]. Furthermore, Pothof et al. [48] reported that UV damage can trigger a cell cycledependent relocalization of Ago2 into stress granules and thus change miRNA expression. In addition, TAp63, the transactivation isoform of p63, regulates miRNA processing by binding to the promoter of Dicer and transactivating its expression [49]. 2.1.3. DNA damage modulates miRNA degradation After DNA damage, miRNA expression can be downregulated via increased degradation. Single-stranded miRNA can be degraded by the 50 –30 exoribonuclease XRN2 or 30 –50 exoribonuclease human polynucleotide phosphorylase [50,51]. Previous studies have shown that the binding of pre-miRNAs to protein components such as MCPIP1 can facilitate the process of pre-miRNA degradation [52]. A recent study reported that the nucleotidyl transferase PAP associated domain containing 5 (PAPD5) and the poly(A)specific ribonuclease PARN can work together to mediate 30 adenylation and subsequent degradation of miR-21 [53]. However, the detailed mechanisms whereby DNA damage can induce miRNA degradation and turnover need to be further investigated. 2.2. LncRNAs LncRNAs are broadly defined as endogenous cellular RNAs longer than 200 nucleotides. These RNAs are poorly conserved and capable of regulating gene expression by various modes, such as chromatin modification, transcriptional regulation and posttranscriptional regulation. Most lncRNAs are transcribed by RNA polymerase II, which is evidenced by Pol II occupancy, the 50 cap structure, histone modifications associated with Pol II transcriptional elongation, and polyadenylation. Based on their proximal adjacent protein-coding genes, lncRNAs are generally divided into five classes: sense, antisense, bidirectional, intronic, and intergenic [54]. LncRNAs show cell type-specific expression and respond to various stimuli, suggesting that their expression is largely influenced by transcriptional activity. Microarray approaches have been used to detect lncRNA expression after DNA damage (Fig. 3). Hung et al. [55] found that DNA damage induces the expression of

Fig. 3. DNA damage induces alteration of lncRNAs by transcriptional control.

five lncRNAs from the CDKN1A promoter. One of the five lncRNAs is p21-associated ncRNA DNA damage activated (PANDA), which is induced in a p53-dependent manner. Huarte et al. [56] discovered that p53 directly binds to the lincRNA-p21 promoter to transcriptionally activate lincRNA-p21 expression. Another p53-dependent lncRNA, TUG1, is transcriptionally activated after DNA damage. TUG1 was upregulated by taurine in non-small cell lung cancer and was found to repress p53-dependent cell cycle regulation [57]. In addition to p53, transcription factor E2F1 transcriptionally activates antisense non-coding RNA in the INK4 locus (ANRIL) in an ATM-dependent manner after DNA damage [58]. These findings suggest that p53 or E2F1 transcriptionally activates lncRNAs, which play key regulatory roles in DDR. Many details regarding the role of lncRNA in DDR remain to be determined, including the mechanisms whereby DDR regulates lncRNA and transcriptional control and the mechanisms whereby lncRNA can alter DDR potentially through lncRNA-mediated protein interactions or lncRNA-mediated transcriptional regulation. 2.3. Other noncoding RNAs In addition to miRNAs and lncRNAs, other non-coding RNAs such as DDRNAs and piRNAs have been shown to be involved in DDR. Recent studies revealed that 21-nucleotide small noncoding RNAs can be produced from the sequences in the vicinity of DSB site in Arabidopsis and in human cells [8,9], and these were thought to be DDRNAs or diRNAs. One report showed that inactivation of Dicer and Drosha results in defective DDR activation. In that study, deficiency of Dicer or Drosha, but not the three GW182 proteins, which are effectors of RNAi-mediated translational repression, impaired the formation and maintenance of DDR foci [8]. Another class of noncoding RNA involved in DDR is piRNAs [3]. piRNAs play an important role in germline development and in maintaining germline DNA integrity. However, whether piRNAs can regulate DDR by controlling chromatin organization, gene transcription, RNA stability, or RNA translation is not well understood; moreover, whether DDR regulates piRNA biogenesis is not known. The answers to these questions may provide mechanistic insight into genomic maintenance in germline cells through piRNA-mediated regulation. 3. Non-coding RNAs regulate DNA damage DDR regulates non-coding RNA expression via multiple mechanisms. Interestingly, a bidirectional regulatory pathway exists between non-coding RNAs and DDR. In response to DNA damage, non-coding RNAs can directly regulate cellular processes involved in DDR by altering their targeting genes, which provides a feedback regulatory loop for non-coding RNA-mediated DDR.


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3.1. miRNAs MiRNAs are required for almost every aspect of cellular responses to DNA damage, including sensing DNA damage, transducing damage signals, repairing damaged DNA, activating cell cycle checkpoints, and inducing apoptosis. 3.1.1. miRNAs regulate DDR sensors H2AX is a well-established sensor protein that can detect and mark damaged DNA by its phosphorylated form (g-H2AX), which provides a molecular platform to assemble proteins involved in DNA damage and repair machinery. Recent studies have shown that miR-24 and miR-138 directly target H2AX to modulate DDR [59,60]. H2AX is a target gene of miR-138. miR-138 overexpression reduces histone H2AX expression and thereby increases chromosomal instability after DNA damage. In addition, overexpression of miR-138 inhibits HR-mediated DNA repair of DSBs and enhances cellular sensitivity to DNA-damaging agents, such as cisplatin, camptothecin, and IR. Transfection of histone H2AX in cells with miR-138 overexpression rescues miR-138-mediated sensitization to cisplatin and camptothecin [59]. These results suggest that miRNAs can regulate upstream DDR signaling. 3.1.2. miRNAs regulate DDR transducers Multiple lines of evidence indicate that in addition to directly targeting sensor proteins of DDR such as H2AX, miRNAs can function as signal transducers by directly targeting kinases involved in DDR. For example, ATM has been shown to be a gene target of a variety of miRNAs, including miR-223, miR-181a, miR26a, miR-27a, miR-214, and miR-18a [61–67]. These miRNAs enhance sensitivity to IR and etoposide by regulating the ATMmediated signaling pathway. Moreover, Chen et al. [68] reported that miR-101 directly targets DNA-PKcs, which can enhance the radiosensitivity of non-small cell lung cancer cells. In addition, Wang et al. [69] reported that miR-185 enhances radiosensitivity by regulating ATR. Collectively, these studies showed that miRNAs regulate DNA damage response by acting as signal transducers.

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3.1.3. miRNAs regulate DDR effectors A wide array of proteins is required to execute the biological effects of DDR, including cell cycle arrest, DNA repair, and apoptosis, which function as effectors of DDR. These proteins work together in a coordinated manner to determine cell fate after DNA damage—i.e., whether the cell cycle should be arrested to allow the repair of damaged DNA or whether cells should undergo apoptosis when the damage is beyond repair. MiRNAs have been shown to modulate DDR by targeting the effectors of DDR. As shown in Fig. 4, miRNAs can control cell cycle progression after DNA damage by targeting CHK1 [70–74], p53 [75,76], retinoblastoma 1 serine phosphates from human chromosome 3 (RBSP3) [77], cyclin D [73,78,79], CDC25a [80–82], p21, CDK2 [83–85], WEE1, PLK1, and so on. One study showed that RBSP3 is a target gene of miR-100. The same study showed that sodium iodide treatment inhibits the expression of miR-100 and thereby upregulates the RBSP3 protein and blocks the transition of FTC cells from the G1 to the S phase [77]. As a major regulator of the cell cycle, cyclin D is a target of miR-34c, which can silence cylin D to prevent benzo[a]pyrene (BaP)-induced malignant transformation [86]. Moreover, miR-424 directly targets CHK1 to block G1/S transition in cervical cancer [72]. Similar to this observation in cervical cancer, miR-506 can directly target CDK4 and CDK6 to induce G1/S cell cycle arrest in ovarian cancer [87]. In line with these studies, miR-545 has been identified as a regulator of cyclin D1 and CDK4, which can induce G0/G1 cell cycle arrest in lung cancer cells [88]. In addition, G2/M phase regulators WEE1, CHK1, and CDK1 are miRNA targets. Their function in regulating G2/M transition can be directly impacted by miRNA pathways [70]. In addition to functioning as regulators of cell cycle effectors, miRNAs are involved in regulating multiple proteins involved in both DSB repair pathways, NHEJ and HRR (Fig. 5). Ku70 and Ku80 are the key repair proteins required for NHEJ repair. Previous studies showed that miR-124 targets Ku70, which improves ischemia/reperfusion-induced brain injury and dysfunction [89]. In parallel, HR repair key protein BRCA1 is targeted by miR-9, which impedes cisplatin-induced DNA damage repair in

Fig. 4. miRNAs modulate cell cycle after DNA damage by targeting key genes involved in cell cycle control.


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Fig. 5. miRNAs modulate NHEJ and HRR DNA repair pathways by targeting key DNA repair protein.

ovarian cancer. Thus, miR-9 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage [90]. Additional miRNAs such as miR-182, miR-146a, and miR-146b-5p have also been found to target BRCA1 [91]. When DNA damage cannot be repaired, cell death is induced via activation of the apoptosis pathway. In addition to regulating p53, miRNAs including miR-365, miR-1915, miR-1271, miR-511, and miR-221/222 are known to target apoptotic proteins such as PUMA, bcl-2, and Bax [92–96]. miRNA-mediated regulation of apoptosis has also been discussed in previous reviews [97,98]. 3.2. lncRNAs Recent studies have revealed an emerging role of lncRNAs in DDR. Four different regulatory models have been proposed for the functions of lncRNAs in DDR through transcriptional control:

signal, decoy, guide, and scaffold (Fig. 6) [54,99]. Increasingly, lncRNAs have been shown to play an indispensable role in cellular responses to DNA damage. 3.2.1. Signal Transcription of individual lncRNAs involved in different biological processes occurs in a space- and time-dependent manner. Thus, lncRNAs can function as molecular markers that signal the space, time, and expression of gene transcription, specifically reflecting the integrative biological outcome of transcription factors and signaling pathways controlling gene expression in space and time. LincRNA p21 is an example of lncRNAs that are involved in DNA damage and cell cycle control. p53-regulated lincRNA p21 expression plays an important role in triggering apoptosis. LincRNA p21 can bind to heterogeneous nuclear ribonucleoprotein K (hnRNP-K), which is a coactivator of

Fig. 6. Four modes of the potential regulatory roles of lncRNAs in transcription in response to DNA damage, including signal, decoy, guide, and scaffold.


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p53-dependent p21 transcription. By binding to hnRNP-K, lincRNA p21 is recruited to the promoters of genes and represses their expression in a p53-dependent manner. Therefore, lincRNA p21 acts as an inhibitor of the p53-dependent transcription response by repressing the transcription of genes that are involved in the apoptosis pathway. After loss of lincRNA p21, hnRNP-K is inappropriately localized at the promoters of p53-repressed genes, which results in deregulated expression and altered chromatin states of polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency [100]. 3.2.2. Decoy One group of lncRNAs does not exert any function except binding and titrating away a protein or RNA target. By decoying proteins and/or RNAs, they may negatively regulate the expression of target genes of these molecules. PANDA locates approximately 5 kb upstream on the antisense strand between the protein-coding p21 (CDKN1A) gene and lincRNA-p21. PANDA is one of the lncRNAs with decoy function, and it regulates cellular responses to DNA damage. PANDA promotes cell cycle arrest via its interaction with the transcription factor NF-YA, thereby limiting the expression of proapoptoic genes. PANDA knockdown increases NF-YA occupancy at the promoter regions of p53-dependent pro-apoptotic genes, including FAS, PUMA, CCNB1, and NOXA, which leads to increased cell death in response to DNA damage [55]. 3.2.3. Guide lncRNAs can also guide RNA-binding proteins to specific target locations. Such lncRNAs can alter gene expression in cis or in trans. CCND lncRNAs are a good example of the function of this type of lncRNAs. CCND lncRNAs are generated in the upstream of the CCND1 promoter after subjecting to genotoxic stress and it is the first lncRNAs found to be responsive to DDR. In response to IR, CCND lncRNAs function in cis to recruit and modulate the activity of transloacted in liposarcoma (TLS), which is an RNA-binding protein. The N-terminal of TLS is responsible for its interaction with two well-known histone acetyltransferases (HATs), CBP and p300. The DDR-responsive CCND lncRNAs are located in the regulatory regions of the CCND1 gene. By recruiting TLS and creating a close-to-open conformation change in TLS, CCND lncRNAs can license the interaction between TLS and CBP/p300, which results in a substrate-specific inhibition of the HAT enzymatic activity and thereby establishes the hypo-acetylation chromatin status and represses CCND1 expression [101]. 3.2.4. Scaffold Another group of lncRNAs can serve as adaptors that serve a scaffold function to assemble different effector molecules. By creating a central protein interaction platform, these lncRNAs can selectively utilize specific signaling components to initiate the desired biological functions in response to different stimuli such as ANRIL. ANRIL has been shown to play a role in the epigenetic regulation of the INK4B-ARF-INK4A locus by directly binding to the INK4b transcript and recruiting the polycomb repressor complex to repress the transcription of genes at this locus [58]. 3.3. Other non-coding RNAs In addition to miRNAs and lncRNAs, other types of non-coding RNAs may be involved in DDR. However, the underlying mechanisms of these non-coding RNAs remains largely unknown. A recent study revealed a novel function of diRNAs in HR-mediated DSB repair that is dependent on the effector protein Ago2 in mammalian cells. DDR-induced diRNAs can guide Ago2 to promote Rad51 recruitment and/or retention at DSBs, which facilitates HR

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repair [102]. Another more recent study reported that endogenous transcript RNA can mediate HR repair with chromosomal DNA in yeast Saccharomyces cerevisiae. The events of HR repair can be initiated by transcript RNA following the repair of a chromosomal DSB occurring either in a homologous but remote locus, or in the same transcript-generating locus [103]. These new findings provide novel mechanistic insights into how non-coding RNAs might regulate DNA repair process. 4. Potential clinical applications of non-coding RNAs Activation of oncogenes promotes replicative stress, inducing DDR in the early phase of tumorigenesis. Moreover, DDR alters the expression profiles of non-coding RNAs to modulate DNA damage repair. Thus, it is reasonable to assume that the dysfunctional regulation of non-coding RNAs may breach the DDR barrier against tumorigenesis. Future research should focus on linking alterations in non-coding RNAs expression with tumorigenesis, particularly for early lesions. Increasingly, studies have shown that tumor tissue and normal tissue exhibit distinct non-coding RNA expression profiles, and the aberrant non-coding RNAs can play an important role in cancer development [104,105]. It is likely that these aberrant non-coding RNAs can be used as potential predictive markers for prognosis and treatment response. More importantly, these non-coding RNAs may also be used as therapeutic targets to develop new strategies for anti-cancer treatment. Aberrant miRNAs have been investigated as prognostic factors in a variety of cancers, including glioblastoma, lung cancer, pancreatic cancer, and breast cancer [106–109]. Moreover, recent clinical studies identified the stable presence of miRNAs in serum, plasma, and other body fluids, and these findings have paved the way for their use as promising biomarkers for diagnosing cancer [109–111]. LncRNAs might also be detected via these non-invasive methods as useful biomarkers. One study found that 47 lncRNAs were differentially expressed between normal lung tissues and tumor samples and 19 lncRNAs were differentially expressed between two subtypes of non-small cell lung cancer (NSCLC) [112]. Thus, lncRNA screening may be beneficial for molecular diagnosis and classification of subtypes in NSCLC. In addition to potentially being used as biomarkers, these aberrant miRNAs and lncRNAs might be used as personalized therapeutic targets. Accumulating experimental evidence has shown that restoring or knocking down specific miRNAs or lncRNAs significantly inhibits cancer cell growth [113]. Furthermore, restoring or knocking down specific miRNAs or lncRNAs can significantly sensitize cancer cells to radiotherapy and chemotherapy [61,113–117]. With advances in new technologies, a number of approaches have been developed to restore or knock down specific miRNAs. We can use locked nucleic acids, anti-miRNA oligonucleotides, miRNA sponges, and antagomirs to knock down specific miRNAs [118–121]. We can also use chemically modified miRNA mimics, adenoviral- or lentiviralbased overexpression, and nanoparticle-based delivery [122]. A recent study showed that AC1MMYR2, which is a specific smallmolecule inhibitor of miR-21, could knock down miR-21 and suppress the proliferation, survival, and invasion of glioblastoma, breast cancer, and gastric cancer cells [123]. Particularly, DDRinduced non-coding RNAs might be useful markers to predict the radio- and chemo-sensitivity of cancer cells. Furthermore, modulation of these non-coding RNAs may also be a useful therapeutic tool to overcome radio- and chemo-resistance. 5. Conclusion In summary, we have discussed the ways in which DDR regulates non-coding RNA expression, which can in turn modulate cellular responses to DNA damage. However, because this is an


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emerging field in DDR research, many key questions need to be further investigated: (1) How do these non-coding RNAs dynamically coordinate DDR in a time- and space-dependent manner? (2) Is there any crosstalk among these non-coding RNAs that may induce DDR feedback via the regulatory loop formed by a group of non-coding RNAs? (3) Do these non-coding RNAs have tissue- and cell-type specificity? (4) How can non-coding RNAs respond to different types of DNA damage? We believe the answers to these questions will not only provide mechanistic insight into DDR but also lead to the development of new strategies for cancer diagnosis, prognosis, and treatment. Conflict of interest We declare that we have no conflict of interest. Acknowledgements Supported by Tianjin Science and Technology Committee (13JCYBJC21700, to Chunzhi Zhang), and by Tianjin Health Bureau (12KG113, to Chunzhi Zhang). References [1] I.A. Shaltiel, M. Aprelia, A.T. Saurin, D. Chowdhury, G.J. Kops, E.E. Voest, R.H. Medema, Distinct phosphatases antagonize the p53 response in different phases of the cell cycle, Proc. Natl. Acad. Sci. U.S.A. 111 (2014) 7313–7318. [2] N.J. Curtin, DNA repair dysregulation from cancer driver to therapeutic target, Nat. Rev. Cancer 12 (2012) 801–817. [3] F. d’Adda di Fagagna, A direct role for small non-coding RNAs in DNA damage response, Trends Cell Biol. 24 (2014) 171–178. [4] P. Fortini, C. Ferretti, E. Dogliotti, The response to DNA damage during differentiation: pathways and consequences, Mut. Res. 743–744 (2013) 160–168. [5] Y. Liu, X. Lu, Non-coding RNAs in DNA damage response, Am. J. Cancer Res. 2 (2012) 658–675. [6] A. Mao, Y. Liu, H. Zhang, C. Di, C. Sun, MicroRNA expression and biogenesis in cellular response to ionizing radiation, DNA Cell Biol. 33 (2014) 667–679. [7] G. Wan, X. Hu, Y. Liu, C. Han, A.K. Sood, G.A. Calin, X. Zhang, X. Lu, A novel non-coding RNA lncRNA-JADE connects DNA damage signalling to histone H4 acetylation, EMBO J. 32 (2013) 2833–2847. [8] S. Francia, F. Michelini, A. Saxena, D. Tang, M. de Hoon, V. Anelli, M. Mione, P. Carninci, F. d’Adda di Fagagna, Site-specific DICER and DROSHA RNA products control the DNA-damage response, Nature 488 (2012) 231–235. [9] W. Wei, Z. Ba, M. Gao, Y. Wu, Y. Ma, S. Amiard, C.I. White, J.M. Rendtlew Danielsen, Y.G. Yang, Y. Qi, A role for small RNAs in DNA double-strand break repair, Cell 149 (2012) 101–112. [10] P. Beli, N. Lukashchuk, S.A. Wagner, B.T. Weinert, J.V. Olsen, L. Baskcomb, M. Mann, S.P. Jackson, C. Choudhary, Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response, Mol. Cell 46 (2012) 212–225. [11] V. Sharma, T. Misteli, Non-coding RNAs in DNA damage and repair, FEBS Lett. 587 (2013) 1832–1839. [12] D. Chowdhury, Y.E. Choi, M.E. Brault, Charity begins at home: non-coding RNA functions in DNA repair, Nat. Rev. Mol. Cell Biol. 14 (2013) 181–189. [13] M.T. van Jaarsveld, M.D. Wouters, A.W. Boersma, M. Smid, W.F. van Ijcken, R.H. Mathijssen, J.H. Hoeijmakers, J.W. Martens, S. van Laere, E.A. Wiemer, J. Pothof, DNA damage responsive microRNAs misexpressed in human cancer modulate therapy sensitivity, Mol. Oncol. 8 (2014) 458–468. [14] J.R. Czochor, P.M. Glazer, microRNAs in cancer cell response to ionizing radiation, Antioxid. Redox Signal. 21 (2014) 293–312. [15] Y. Wang, T. Taniguchi, MicroRNAs and DNA damage response: implications for cancer therapy, Cell Cycle 12 (2013) 32–42. [16] G. Zhang, L. Sun, X. Lu, Z. Chen, P.J. Duerksen-Hughes, H. Hu, X. Zhu, J. Yang, Cisplatin treatment leads to changes in nuclear protein and microRNA expression, Mut. Res. 746 (2012) 66–77. [17] M.D. Wouters, D.C. van Gent, J.H. Hoeijmakers, J. Pothof, MicroRNAs, the DNA damage response and cancer, Mut. Res. 717 (2011) 54–66. [18] G. Liang, G. Li, Y. Wang, W. Lei, Z. Xiao, Aberrant miRNA expression response to UV irradiation in human liver cancer cells, Mol. Med. Rep. 9 (2014) 904–910. [19] L. He, X. He, L.P. Lim, E. de Stanchina, Z. Xuan, Y. Liang, W. Xue, L. Zender, J. Magnus, D. Ridzon, A.L. Jackson, P.S. Linsley, C. Chen, S.W. Lowe, M.A. Cleary, G.J. Hannon, A microRNA component of the p53 tumour suppressor network, Nature 447 (2007) 1130–1134. [20] U. Mert, E. Ozgur, D. Tiryakioglu, N. Dalay, U. Gezer, Induction of p53-inducible microRNA miR-34 by gamma radiation and bleomycin are different, Front. Genet. 3 (2012) 220. [21] N. Okada, C.P. Lin, M.C. Ribeiro, A. Biton, G. Lai, X. He, P. Bu, H. Vogel, D.M. Jablons, A.C. Keller, J.E. Wilkinson, B. He, T.P. Speed, L. He, A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression, Genes Dev. 28 (2014) 438–450.

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