This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Event: 1980
Key Event Title
Increased microRNA expression
Short name
Biological Context
Level of Biological Organization |
---|
Cellular |
Cell term
Organ term
Key Event Components
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
DNA damage and metastatic breast cancer | KeyEvent | Usha Adiga (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
Adult, reproductively mature | Moderate |
Sex Applicability
Term | Evidence |
---|---|
Female | Moderate |
Key Event Description
Biological state
The elevation of microRNA (miRNA) levels as a consequence of mutations and chromosomal aberrations is a multifaceted outcome stemming from the intricate regulatory dynamics of gene expression. These genetic alterations can trigger a cascade of events that influence miRNA expression. Mutations and aberrations in regulatory regions can lead to increased transcription of miRNA genes, augmenting the production of precursor miRNAs. Moreover, copy number changes resulting from chromosomal aberrations, such as gene amplification, can amplify the output of miRNA genes, ultimately boosting mature miRNA levels. Disruptions in genes responsible for miRNA processing can perturb the biogenesis pathway, leading to the accumulation of precursor miRNAs and subsequent rise in mature miRNA abundance. In parallel, altered regulatory interactions and epigenetic modifications brought about by genetic changes can free miRNA genes from their constraints, promoting enhanced expression. Additionally, miRNA-mediated feedback loops, influenced by mutations, can indirectly influence miRNA levels. This complex interplay underscores how genetic alterations can reshape the miRNA landscape, potentially influencing downstream gene expression patterns and contributing to diverse cellular outcomes and disease processes.
Genome integrity must be maintained for the proper functioning and survival of an organism. There has been an efficient and rapid response developed by the eukaryotic cells to DNA damage to overcome the harmful effects. As soon as the DNA damage or replication arrest is detected, the activation of cell cycle checkpoint and stopping the progress of the cell cycle thus providing time for the cell to repair the DNA damage. The response to DNA damage also leads to transcriptional regulation, activation of DNA repair, and, in severe cases, initiation of apoptosis (Harper, J.W., and Elledge, S.J. , 2007). Expression of miRNAs may be regulated by the DNA damage response. A study reported that that micro RNA expression is a a partially ATM / ATR-independent manner(Pothof, J. et al , 2009). Subsequent studies have shown that the tumor suppressor p53 promotes PrimeRNA processing via RNA helicase p68 (Suzuki, H.I et al, 2009).
Han et al evaluated miRNA expression pattern in a DNA damage regulatory protein, DDX1 in controls, as well in DDX1-knockdown U2OS cells with the help of reverse transcription quantitative-PCR (qRT-PCR) and human miRNA array (Han C et al, 2014). The study noticed a significant reduction in the expression levels of a subset of miRNAs -200 family such as miR-200a, miR-200b, miR-200c, miR-141 and miR-429 (cut-off >2-fold).d miR-429). The ovarian cancer genomics study revealed a 8-miRNA signature that defines the mesenchymal subtype of serous ovarian cancer (Yang Y, et al, 2011). Among the eight miRNAs, miR-200a, miR-29c, miR-141 and miR-101 were significantly dependent on DDX1, suggesting that DDX1 may play a role in ovarian tumor progression. Nuclear run-on assays were performed to determine whether DDX1 regulates the miRNA expression at transcriptional or post-transcriptional levels, No notable differences were seen in the transcription of pri-miR-200s from the two miR-200 gene clusters (miR-200a/200b/429 and miR-200c/141) in the control and DDX1-silenced cells . However, in the DDX1-knockdown U2OS cells, the levels of mature DDX1-dependent miRNAs, but not control miR-21, were significantly decreased. Due to the potential inhibition of miRNA processing activity, primary transcripts of the DDX1-dependent miRNAs were accumulated. Conversely, these DDX1-dependent miRNAs were up-regulated in the DDX1- overexpressing cells. The above findings suggested that expression of specific miRNAs was promoted by DDX1 at the post-transcriptional level.
Biological compartments:
Cellular, nucleus, cytoplasm and mitochondria
General role in biology:
MicroRNAs (miRNAs) are endogenous non-coding RNAs that contain approximately 22 nucleotides. They function as major regulators of various biological processes, and their dysregulation is associated with many diseases, including cancer.
Cells trigger a specific cellular responses to preserve the integrity of the genome. The DNA damage response (DDR) is one among them along with several distinct DNA repair pathways.Normal cells need to repair DNA damage through various repair mechanisms or induce apoptosis and cell cycle arrest if repair is not possible [Jackson SP and Bartek J, 2009]. Genomic instability and mutagenesis are brought about by the disruption of repair mechanisms.DNA damage response (DDR) determines the fate of the cell and controls microRNAs expression. This will in turn regulate important components of the DNA repair machinery. Various reports suggest the key role of miRNA in the regulation of the DDR [d’Adda di Fagagna F, 2014 and WeiW et al 2012].The DDR and DNA damage are known regulators of miRNA expression [Sharma V et al 2013 and Chowdhury D et al 2013]. Several studies have shown that the cellular sensitivity to chemotherapeutic drugs is affected by DDR- miRNA network.[ van Jaarsveld MT et al 2014].
A bidirectional relationship between miRNAs and the DDR has been suggested by studies. The DDR is a known regulator of miRNA expression at both transcriptional and post-transcriptional levels, and miRNA-mediated gene silencing has been shown to modulate the activity of the DDR [d’Adda di Fagagna F, 2014 ; WeiW et al 2012 and Han C et al 2012]. A unique set of miRNAs as well as a common core miRNA signature are activated depending on DNA damage type and level, suggesting that miRNAs regulate the DDR by mechanisms based on the type and/or the intensity of DNA damage [Han C et al 2012]. miRNAs expression may be regulated by transcription factors either binding directly to miRNA promoters and modulating their transcriptional activity, or by modifying the expression of miRNA processing machinery components.
Studies have widely explored the TP53-mediated transcriptional pathways regulating miRNA expression following DNA damage. miRNA-34a-c is induced by DNA damage and oncogenic stress, is one of the transcriptional target of the tumor suppressor TP53 [Hermeking H et al 2012]. TP53 directly binds to the promoter of miRNA-34 and activates transcription. Micro RNA-34 has been reported to repress the mRNA transcripts of several genes involved in the regulation of cell cycle, cell proliferation and survival, such as BCL2, CCND1 CCNE2, MYC, CDK4, CDK6 and SIRT1 [Hermeking H et al 2012]. Activation of miRNA-34a promotes TP53-mediated apoptosis, cell cycle arrest or senescence [Hermeking H et al 2012]. miRNA-34a may target SIRT1, form a positive feedback loop of the acetylation of TP53, expression of its transcriptional targets, regulating cell cycle and apoptosis [Hermeking H et al 2012]. The alternative pathway involving p38 MAPK signaling also induces miR-34c [Cannell IG et al 2010]. Inhibition of miRNA 34 prevents the DNA damage induced cell cycle arrest and results in an increased DNA synthesis [Cannell IG et al 2010].
DNA damage promotes the TP53-dependent upregulation of miRNA-192, miRNA-194 and miRNA-215. The genomic region surrounding the miRNA-194/miRNA-215 cluster contains a putative TP53-binding element, indicating that these miRNAs are transcriptionally activated by TP53 [Hermeking H et al 2012]. The expression of miRNA-192 and miRNA-215 induces cell cycle arrest and targets several transcripts involved in cell cycle checkpoints [Georges SA et al 2008].
MYC and E2F, are the two other transcription factors involved in DNA damage- induced cell cycle checkpoints, that regulate the expression of several miRNAs. Both factors induce transcription of the miRNA-17-92 cluster that forms a feedback loop by inhibiting E2F expression [Aguda BD et al 2008]. E2F transcription factors are repressed by several other miRNAs, including miRNA-106a-92 and miRNA-106b-25 cluster members, miRNA-210, miRNA-128, miRNA-34 and miRNA-20 [Wan G et al 2011].
DNA damage upregulates several miRNAs, including miRNA-16-1, miRNA-143 and miRNA-145. [Suzuki HI et al 2009]. Most TP53 mutations found in cancers are located in a domain required for miRNA processing and transcriptional activity [Suzuki HI et al 2009]. Thus, loss of TP53 functions in miRNAs transcription and processing might contribute to cancer progression. Considering that some miRNAs are reduced after DNA damage in an ATM-dependent manner, ATM could be also involved in inhibitory pathways that downregulate miRNA expression [Wang Y et al 2013]. These findings support the existence of a critical link between the DDR and miRNA processing pathway.
In the DNA damage response, post-transcriptional processing of miRNAs is also regulated. It was reported that DNA damage led to increased levels of some pre-miRNAs and mature miRNAs without significant changes of levels of their primary transcripts, suggesting posttranscriptional mechanisms could contribute to the induction of certain miRNAs under DNA damage stress [Zhang X, et al 2011]. There appears to be functional connections between DNA damage response and miRNA processing and maturation.
Micro RNA - 18a, miR-100, miR-101, miR-181, and miR-421, have been implicated as novel regulators to control the protein level of ATM (Majid S et al 2010). BRCA1, a critical tumor suppressor, BRCA1, is also recruited to DNA damage lesions, where it facilitates DNA repair. The level of BRCA1 is regulated by miR-182, miR-146a, and 146b-5p (Matsui M et al 2013).
The tumor suppressor p53 has a central role in the activation of genes in multiple pathways, including cell cycle regulation, tumor suppression, and apoptosis. Micro RNA-125b and miR-504 have been identified as negative regulators of p53 in several types of human cells (Kreis S et al 2008 and Wang J et al 2012).
The available evidence suggests that DNA damage signaling participates in miRNA biogenesis by regulating both transcriptional and post-transcriptional mechanisms. Further studies can through light on the correlation between DNA damaging signaling and miRNA processing. The majority of the studies have examined the miRNA regulation in response to DNA damage and have focused on events that occur in the nucleus. It is important to extend the investigations in understanding the contribution of cytoplasmic regulation of miRNA biogenesis following DNA damage. It is very interesting to determine whether DNA damage signals can modulate the turnover, stabilization, modification, and degradation of miRNAs.
How It Is Measured or Detected
Method/ measurement reference |
Reliability |
Strength of evidence |
Assay fit for purpose |
Repeatability/ reproducibility |
Direct measure |
|
Human cell line |
Western blotting,clonal survival assay,FACs(van Jaarsveld MT et al 2014) |
Yes |
Strong |
Yes |
Yes |
Yes |
Mice |
Free radicCyQuant cell Proliferation assay (Abdelfattah, N. et al 2018) |
Yes |
Strong |
Yes |
Yes |
Yes |
RNA sequence analysis,Immuno staining,immunoblotting,Flowcytometry,COMET assay,qRT PCR(Liu Z et al 2017) |
Yes |
Strong |
Yes |
Yes |
Yes |
|
Microarray (Zhang X et al 2011) |
Yes |
Strong |
Yes |
Yes |
Yes |
|
qRT PCR,RIP assay,Immunogold EM(Wan G et al 2013) |
Yes |
Strong |
Yes |
Yes |
Yes |
|
Canine |
micro array(Bulkowska M et al 2017) |
Yes |
Strong |
Yes |
Yes |
Yes |
Domain of Applicability
Regulation of miRNA expression by DNA replication,damage and repair responses,transcription and translation has been proved in animals like mice,canine and cell line experiments.
References
Abdelfattah, N., Rajamanickam, S., Panneerdoss, S., Timilsina, S., Yadav, P., Onyeagucha, B. C., ... & Rao, M. K. (2018). MiR-584-5p potentiates vincristine and radiation response by inducing spindle defects and DNA damage in medulloblastoma. Nature communications, 9(1), 1-19. |
Aguda, B. D., Kim, Y., Piper-Hunter, M. G., Friedman, A., & Marsh, C. B. (2008). MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proceedings of the National Academy of Sciences, 105(50), 19678-19683. |
Bulkowska, M., Rybicka, A., Senses, K. M., Ulewicz, K., Witt, K., Szymanska, J., ... & Krol, M. (2017). MicroRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours. BMC cancer, 17(1), 1-17. |
Cannell, I. G., Kong, Y. W., Johnston, S. J., Chen, M. L., Collins, H. M., Dobbyn, H. C., ... & Bushell, M. (2010). p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication. Proceedings of the National Academy of Sciences, 107(12), 5375-5380. |
Chowdhury, D., Choi, Y. E., & Brault, M. E. (2013). Charity begins at home: non-coding RNA functions in DNA repair. Nature reviews Molecular cell biology, 14(3), 181-189. |
di Fagagna, F. D. A. (2014). A direct role for small non-coding RNAs in DNA damage response. Trends in cell biology, 24(3), 171-178. |
Georges, S. A., Biery, M. C., Kim, S. Y., Schelter, J. M., Guo, J., Chang, A. N., ... & Chau, B. N. (2008). Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215. Cancer research, 68(24), 10105-10112. |
Han, C., Liu, Y., Wan, G., Choi, H. J., Zhao, L., Ivan, C., ... & Lu, X. (2014). The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell reports, 8(5), 1447-1460. |
Han, C., Wan, G., Langley, R. R., Zhang, X., & Lu, X. (2012). Crosstalk between the DNA damage response pathway and microRNAs. Cellular and molecular life sciences, 69(17), 2895-2906. |
Harper, J. W., & Elledge, S. J. (2007). The DNA damage response: ten years after. Molecular cell, 28(5), 739-745. |
Hermeking, H. (2012). MicroRNAs in the p53 network: micromanagement of tumour suppression. Nature reviews cancer, 12(9), 613-626. |
Jackson SP, Bartek J. (2009). The DNA-damage response in human biology and disease. Nature, 461,1071-8 |
Kreis, S., Philippidou, D., Margue, C., & Behrmann, I. (2008). IL‐24: a classic cytokine and/or a potential cure for cancer?. Journal of cellular and molecular medicine, 12(6a), 2505-2510. |
Liu, Z., Zhang, C., Khodadadi-Jamayran, A., Dang, L., Han, X., Kim, K., ... & Zhao, R. (2017). Canonical microRNAs enable differentiation, protect against DNA damage, and promote cholesterol biosynthesis in neural stem cells. Stem cells and development, 26(3), 177-188. |
Majid, S., Dar, A. A., Saini, S., Yamamura, S., Hirata, H., Tanaka, Y., ... & Dahiya, R. (2010). MicroRNA‐205–directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer, 116(24), 5637-5649. |
Matsui, M., Chu, Y., Zhang, H., Gagnon, K. T., Shaikh, S., Kuchimanchi, S., ... & Janowski, B. A. (2013). Promoter RNA links transcriptional regulation of inflammatory pathway genes. Nucleic acids research, 41(22), 10086-10109. |
Pothof, J., Verkaik, N. S., Van Ijcken, W., Wiemer, E. A., Ta, V. T., Van Der Horst, G. T., ... & Persengiev, S. P. (2009). MicroRNA‐mediated gene silencing modulates the UV‐induced DNA‐damage response. The EMBO journal, 28(14), 2090-2099. |
Sharma, V., & Misteli, T. (2013). Non-coding RNAs in DNA damage and repair. FEBS letters, 587(13), 1832-1839. |
Suzuki, H. I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., & Miyazono, K. (2009). Modulation of microRNA processing by p53. Nature, 460(7254), 529-533. |
Suzuki, H. I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., & Miyazono, K. (2009). Modulation of microRNA processing by p53. Nature, 460(7254), 529-533. |
van Jaarsveld, M. T., Wouters, M. D., Boersma, A. W., Smid, M., van IJcken, W. F., Mathijssen, R. H., ... & Pothof, J. (2014). DNA damage responsive microRNAs misexpressed in human cancer modulate therapy sensitivity. Molecular oncology, 8(3), 458-468. |
van Jaarsveld MT, Wouters MD, Boersma AW, Smid M, van Ijcken WF, Mathijssen RH, Hoeijmakers JH, Martens JW, van Laere S, Wiemer EA, Pothof J. (2014) .DNA damage responsive microRNAs misexpressed in human cancer modulate therapy sensitivity. Mol Oncol. 8(3), 458-68. |
Wan, G., Mathur, R., Hu, X., Zhang, X., & Lu, X. (2011). miRNA response to DNA damage. Trends in biochemical sciences, 36(9), 478-484. |
Wan, G., Zhang, X., Langley, R. R., Liu, Y., Hu, X., Han, C., ... & Lu, X. (2013). DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway. Cell reports, 3(6), 2100-2112. |
Wang, J., & Li, L. C. (2012). Small RNA and its application in andrology and urology. Translational andrology and urology, 1(1), 33. |
Wang, Y., & Taniguchi, T. (2013). MicroRNAs and DNA damage response: implications for cancer therapy. Cell cycle, 12(1), 32-42. |
Wei, W., Ba, Z., Gao, M., Wu, Y., Ma, Y., Amiard, S., ... & Qi, Y. (2012). A role for small RNAs in DNA double-strand break repair. Cell, 149(1), 101-112. |
Yang, Y., Ahn, Y. H., Gibbons, D. L., Zang, Y., Lin, W., Thilaganathan, N., ... & Kurie, J. M. (2011). The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200–dependent pathway in mice. The Journal of clinical investigation, 121(4), 1373-1385. |
Zhang, X., Wan, G., Berger, F. G., He, X., & Lu, X. (2011). The ATM kinase induces microRNA biogenesis in the DNA damage response. Molecular cell, 41(4), 371-383. |
Zhang, X., Wan, G., Berger, F. G., He, X., & Lu, X. (2011). The ATM kinase induces microRNA biogenesis in the DNA damage response. Molecular cell, 41(4), 371-383. |