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Event: 1980

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased micro RNA expression

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increase,miRNA levels
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mice Mus sp. Moderate NCBI
human and other cells in culture human and other cells in culture Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult, reproductively mature Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Female Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Biological state

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

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

List of the literature that was cited for this KE description. More help

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 communications9(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 Sciences105(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 cancer17(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 Sciences107(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 biology14(3), 181-189.

di Fagagna, F. D. A. (2014). A direct role for small non-coding RNAs in DNA damage response. Trends in cell biology24(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 research68(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 reports8(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 sciences69(17), 2895-2906.

Harper, J. W., & Elledge, S. J. (2007). The DNA damage response: ten years after. Molecular cell28(5), 739-745.

Hermeking, H. (2012). MicroRNAs in the p53 network: micromanagement of tumour suppression. Nature reviews cancer12(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 medicine12(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 development26(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. Cancer116(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 research41(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 journal28(14), 2090-2099.

Sharma, V., & Misteli, T. (2013). Non-coding RNAs in DNA damage and repair. FEBS letters587(13), 1832-1839.

Suzuki, H. I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., & Miyazono, K. (2009). Modulation of microRNA processing by p53. Nature460(7254), 529-533.

Suzuki, H. I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., & Miyazono, K. (2009). Modulation of microRNA processing by p53. Nature460(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 oncology8(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 sciences36(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 reports3(6), 2100-2112.

Wang, J., & Li, L. C. (2012). Small RNA and its application in andrology and urology. Translational andrology and urology1(1), 33.

Wang, Y., & Taniguchi, T. (2013). MicroRNAs and DNA damage response: implications for cancer therapy. Cell cycle12(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. Cell149(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 investigation121(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 cell41(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 cell41(4), 371-383.