This Key Event Relationship 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.
Relationship: 2609
Title
Increase, Mutations leads to Increase,miRNA levels
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
DNA damage and mutations leading to Metastatic Breast Cancer | adjacent | Moderate | Moderate | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Female | High |
Life Stage Applicability
Term | Evidence |
---|---|
Not Otherwise Specified | Not Specified |
Key Event Relationship Description
Upstream event: increased, mutations
Downstream event: increased miRNA
The Key Event Relationship (KER) depicted involves a chain of events associated with genetic changes and molecular responses. The upstream event is characterized by "Increase in Mutations," indicating a heightened occurrence of changes in the DNA sequence, structure, or arrangement. These mutations can arise from various factors, such as environmental exposures, errors during DNA replication, or DNA repair deficiencies.
The downstream event in this KER is the "Increase in miRNA levels." As a consequence of increased mutations, there is an elevation in the levels of microRNAs (miRNAs), which are small non-coding RNA molecules that play a role in regulating gene expression. The alterations in DNA resulting from mutations can influence the expression of miRNAs, leading to changes in their abundance.
This KER suggests a potential link between genetic changes and miRNA regulation. It highlights the intricate molecular interactions within the cell, where mutations in the genome can impact miRNA expression patterns. Understanding this relationship contributes to a broader understanding of how genetic alterations can influence gene expression and cellular responses.
Evidence Collection Strategy
Adhering to OECD guidelines, a systematic evidence collection approach was implemented to substantiate the Key Event Relationship (KER) "Increase in Mutations leads to Increase in miRNA levels." Initial evidence was obtained through molecular assays that quantified and characterized mutations induced by genotoxic agents. Whole-genome sequencing, mutation-specific PCR, and mutational profiling elucidated the nature and frequency of mutations, providing direct support for the first part of the relationship. Complementary mechanistic studies explored the molecular pathways linking mutations to changes in miRNA levels, shedding light on potential regulatory mechanisms involved. Bioinformatics analyses identified potential miRNA targets associated with the mutated genes.
To establish the subsequent increase in miRNA levels, expression profiling techniques were employed, including microarray and next-generation sequencing. These approaches enabled the quantification of miRNA abundance across various experimental conditions and validated the miRNAs that exhibited altered expression in response to mutations. Additionally, cross-species and cross-strain comparisons enhanced the robustness of the evidence.
Case-control studies involving both in vitro and in vivo models, as well as human populations exposed to genotoxic agents, provided real-world relevance to the KER. These studies revealed a significant correlation between increased mutagenesis and altered miRNA expression profiles, reinforcing the mechanistic underpinnings of the relationship.
By integrating data from diverse sources, conducting mechanistic investigations, and aligning results with OECD principles, a comprehensive and substantiated evidence base was established for the KER "Increase in Mutations leads to Increase in miRNA levels."
Evidence Supporting this KER
Evidences suggest that transcription pathway for miRNAs is regulated in the DNA damage response (DDR). The tumour suppressor p53 is a well-known transcription factor that is activated in response to DNA damage and causes cell growth arrest, promotes apoptosis, inhibits angiogenesis, and mediates DNA repair (Meek et al., 2009). Global miRNA expression investigations identified the miRNA components of p53 transcriptional pathways and demonstrated that a cohort of miRNAs are up-regulated in a p53-dependent manner following DNA damage. The miR-34 family (miR-34a, miR-34b/c) was the first transcriptional target of p53 to be discovered. p53 directly transactivates miR-15a/16-1, miR-29, miR-107, miR-145, miR-192, miR-194, miR-215, and miR-605 in addition to the miR-34 family.
Biological Plausibility
Various transcription factors regulate miRNA expression.The p53 protein also functions as a transcriptional repressor by binding to miRNA promoters and preventing the recruitment of transcriptional activators.For example, p53 prevents the TATA-binding protein from binding to the TAATA site in the promoter of the miR-17-92 cluster gene, suppressing transcription. Under hypoxic conditions, the miR-17-92 cluster is suppressed by a p53-dependent mechanism, making cells more susceptible to hypoxia-induced death (Yan et al.,2009). Cells can amplify the p53 signal by fine-tuning the p53 signalling pathway and the miRNA network, which improves cell sensitivity to external signals.
Other DNA damage-responsive transcription factors, such as NF-kB, E2F, and Myc, are also involved in miRNA transcription regulation. Both E2F and Myc promote miR-17-92 cluster transcription, which reduces E2F and Myc expression, establishing an autoregulatory negative feedback loop. Furthermore, Myc-induced miRNAs have an impact on cell proliferation and cell fate in Myc-mediated cells (Kim et al.,2010). Myc-induced miR-20a, for example, targets cdkn1a, a gene that encodes a negative regulator of cell-cycle progression, while Myc-induced miR-221 and miR-222 target the CDKN1b and CDKN1c genes, respectively, that trigger cell-cycle arrest. Little is currently known about how miRNA gene expression is transcriptionally regulated due to a lack of basic information about miRNA gene structure. Global prediction and verification of promoter regions of miRNA genes would allow us to further explore the functional interaction of transcriptional machinery and epigenetic miRNA regulation. p53 regulates miRNA maturation not only during transcription but also during processing of initial miRNA transcripts, resulting in crosstalk between the p53 network and the DDR's miRNA biogenesis machinery. Many p53-regulated miRNAs target proteins in the DDR, such as cell cycle progression and apoptosis, to affect the DDR.
Empirical Evidence
There are findings that strongly link the different elements of DNA damage and repair events to the expression of miRNA.
- Zhang and coworkers examined genome-wide mature miRNA expression in Atm+/+ and Atm-/- littermate mouse embryonic fibroblasts to see how miRNAs are regulated in the DNA damage response (MEFs)(Zhang et al.,2011).
- MEFs were given neocarzinostatin (NCS), a radiomimetic medication that causes DSBs (Ziv et al., 2006). Mouse miRNA microarray analysis was used to determine miRNA expression profile in each sample, which was done at several time points (0–24 hr). As many as 71 distinct miRNAs were found to be considerably (2-fold) upregulated in the NCS-treated Atm+/+ MEFs, but not in the corresponding Atm-/- MEFs, implying that DNA damage stress causes broad-spectrum changes in miRNA expression.
- The functioning of the Atm gene is required for the induction of these miRNAs. The DNA damage induction of these miRNAs was entirely eliminated when ATM was knocked out of the Atm-/- MEFs, implying that ATM is a critical regulator of KSRP activity in miRNA synthesis.
- To see if DNA damage enhances the transcription of these miRNAs, researchers used quantitative reverse-transcriptase PCR (RT-PCR) using primer sets built particularly for pri-miRNAs to look at the expression levels of primary miRNA transcripts (pri-mRNAs) in both Atm+/+ and Atm-/- MEFs. Regardless of ATM status, these pri-miRNAs did not show any significant induction or reduction (50 percent change) in transcription levels during the DNA damage response.
- The study used a pair of human fibroblast cell lines with proficient (GM0637) or deficient (GM9607) ATM to assess the levels of six representative mature miRNAs that were randomly selected out of the pool for both ATM- and KSRP-induced miRNAs to confirm that DNA damage-mediated miRNA induction in MEFs was not species specific.
- Following NCS treatment, the levels of these miRNAs increased dramatically in ATM-proficient cells but not in ATM-deficient cells, matching the findings from MEFs. DNA damage was not induced by the control miR-218, which is not regulated by ATM or KSRP.
- After DNA damage, -KSRP was necessary for miRNA induction. When KSRP was knocked out, the induction of these miRNAs was significantly reduced, demonstrating a functional connection between KSRP and ATM in miRNA synthesis.
- According to Wan et al., regulatory RNA-binding proteins in the Drosha and Dicer complexes, such as DDX5 and KSRP, drive posttranscriptional processing of primary and precursor miRNAs after DNA damage. The findings show that nuclear export of pre-miRNAs is increased in an ATM-dependent manner after DNA damage. The ATM-activated AKT kinase phosphorylates Nup153, a main component of the nucleopore, resulting in enhanced interaction between Nup153 and Exportin-5 (XPO5) and increased nuclear export of pre-miRNAs. These findings demonstrate that DNA damage signalling is important for miRNA transport and maturation.
- To test the DNA-damage induction of miRNAs in human cells, researchers looked at mature miRNA expression in human fibroblast GM0637 cells treated with the radiomimetic drug neocarzinostatin (NCS) in the presence or absence of the ATM inhibitor KU55933.
- In agreement with previous reports showing that ATM-activated p53 and KSRP promote miRNA expression (Suzuki et al., 2009; Zhang et al., 2011), the study found 61 p53-dependent miRNAs and 29 KSRP-dependent miRNAs among the ATM-induced miRNAs.
- The study also examined the levels of different forms of miRNAs (pri- miRNAs, pre-miRNAs, and mature miRNAs) selected from the ATM-induced miRNAs, including KSRP-dependent miRNAs (let-7a, 15a, 15b, 16, 125b, 21, 27b, 98, and 199a), p53- dependent miRNAs (34a), and KSRP/p53-independent miRNAs (181a, 382, and 338).
- As a control, miR-218, which is unaffected by DNA damage, was also included in the examination. With the exception of miR-34a, which is known to be transactivated by p53, there were no significant increases in expression of primary transcripts for these miRNAs following DNA damage. -These results suggest that DNA damage may promote posttranscriptional maturation of the miRNAs.
- Neither KSRP nor p53 were required for the expression of miR-181a, miR-382, or miR-338. Stable knockdown of KSRP or p53 could not prevent their induction following DNA damage, but knockdown of ATM did, indicating that the increased miRNAs in the DDR are accounted for by another ATM-dependent mechanism. The miR-34a and miR-21 controls were reliant on p53 and KSRP, respectively.
- These findings imply that DNA damage may increase miRNA maturation after transcription. Neither KSRP nor p53 were required for the expression of miR-181a, miR-382, or miR-338. Stable knockdown of KSRP or p53 could not prevent their induction following DNA damage, but knockdown of ATM did, indicating that the increased miRNAs in the DDR are accounted for by another ATM-dependent mechanism. As previously observed (He et al., 2007; Trabucchi et al., 2009), the controls miR-34a and miR-21 were reliant on p53 and KSRP, respectively.
- A group of miRNAs is induced in an ATM-dependent way after DNA damage. Prior to NCS (500 ng/ml) treatment, human fibroblast GM0637 (ATM-proficient) cells were pretreated with ATM inhibitor KU55933 (10 mM) or DMSO. For microarray analysis, cells were taken 4 hours after NCS treatment.
- There was an increase in miRNA levels as well as a drop in miRNA levels.
- The miRNA expression profile from GM0637 cells treated with DMSO or ATM inhibitor was used to identify ATM-dependent (ATM-IN/Ctrl 0.67) and ATM-independent (ATM-IN/Ctrl > 0.67) miRNAs.
- Human Mammary Epithelial progenitor Cells (HMEpC) and Human Small Airway Epithelial progenitor Cells (HSAEpC) were cultivated. Cells were cultivated to population doubling 5 before being aliquoted and frozen in Promocell culture media, which contained 10% DMSO and 5% Human Serum Albumin (HSA, Octalbine). All tests used cells cultivated from a freshly thawed vial and expanded until population doubling was reached. Up to 16 population doublings, the HMEpC/HSAEpC maintained their proliferation characteristics (Jaarsveld et al,.2014)
- As previously stated, miRNA RT-qPCR expression analysis was performed on 8 normal breast tissue samples and 84 breast tumour tissue samples utilising microfluidic cards (A&B TLDA arrays, Applied Biosystems) (Van der Auwera et al., 2010).
- MiRNA microarray analysis was carried out on i.untreated and cisplatin/IR treated HMEpC and HSAEpC cells (4 replicates for each condition), (ii) 18 lung tumour tissue tissue samples and 14 adjacent 'normal' lung tissue samples (representing NSCLC subtypes), and (iii) 52 breast cancer cell lines (Riaz et al., 2013) and 12 lung cancer cell lines. RNA Bee was used to isolate total —-RNA (Bio- Connect, the Netherlands). One mg of RNA was hybridised with an Exiqon LNATM-based probeset (versions 10 and 7 for cell lines and lung tissue, respectively), and spotted in duplicate on Nexterion E slides (Pothof et al., 2009).
- The severity of DNA damage determines the outcome of DDR signalling, i.e. repair and survival or apoptosis/senescence. Since there is evidence in the literature that all these branches within the DDR can be defective in cancer, conditions were established to identify miRNAs that are regulated upon DNA damage in general, independent of biological outcome.
- Two genotoxic therapeutic agents (cisplatin and IR) were used for which a dose was determined that allows for cellular recovery after DNA damage and a dose that induces primarily cell death or senescence.
- To define the conditions for recovery clonal survival assay was used, which determines the capacity of individual cells to recover and form colonies after DNA damage.
- 0.25 mM cisplatin or 1.5 Gy IR were chosen, both resulting in a 50% reduction of HMEpC colony formation , thus 50% of all initially damaged cells can still grow out into a colony within 10 days. --As expected, these conditions activate the DDR and induce cell cycle arrest
- Following that, a higher dose at which the cells suffer apoptosis following cisplatin treatment was determined using an MTT assay. HMEpC viability was reduced by 50% after 48 hours of treatment with 15 mM cisplatin, which was accompanied by lower cellular PARP1 levels, an apoptosis marker. It's worth noting that at this concentration, all cells will eventually die. In contrast to cisplatin, a high dose of IR caused cellular senescence rather than apoptosis, which has no effect on cellular viability as assessed by the MTT experiment.
- HMEpCs were treated with low and high doses of cisplatin and IR to characterise the miRNA response to DNA damage. Total RNA was isolated 6 hours, 12 hours, and 24 hours after the commencement of treatment for each genotoxic treatment and dose based on miRNA kinetics after DNA damage treatment (Pothof et al., 2009; Zhang et al., 2011). MiRNA profiling was carried out on 725 human miRNAs utilising miRNA arrays with Locked Nucleic Acid-based capture probes. Before normalisation, the reproducibility between biological replicates (n 14 4) was examined, revealing that the correlation between replicates was higher than that between non-replicates. After normalisation, condition-specific regulation of miRNAs was shown to be dependent on the kind of genotoxic stress and dose, as well as miRNAs that showed oppo-site regulation after IR and cisplatin treatment.
- General miRNA responders to DNA damage, i.e. significantly regulated miRNAs across all genotoxic conditions per time point were focused.Several general DDR miRNAs were identified and most were regulated at 6 h and 12 h after treatment , which is in agreement with published miRNA expression kinetics after DNA damage (Pothof et al., 2009;). In conclusion, the study could identify several miRNAs that can be characterized as general responders to genotoxic cancer treatments in HMEpCs.
Uncertainties and Inconsistencies
In response to stressors like as ionising radiation, miRNAs are differently regulated. When exposed to IR, miRNA expression is frequently disrupted. Some miRNAs are induced by IR, while others are suppressed, a decision that is likely based on the target genes implicated. This figure summarises the miRNAs mentioned in this review whose expression changes in response to IR. Lists of miRNAs whose induction or repression has been detected are on the left and right, respectively. MiRNAs are in the middle, and both induction and repression have been found in many cell types. The centre contains the biggest group of miRNAs, demonstrating how diverse the miRNA profile can be from one cell type to the next. Bold miRNAs play a role in several parts of the DDR.
Induced miRNAs were reported by some studies (Cha et al.,2009;Chaudhary et al 201; Chaudhary et al 2012; Chaudhary et al 2013;Kwon et al.,2013;Mueller et al.,2013;Shin et al.,2009;Sokolov et al.,2012;Wagner et al.,2010),whereas repressed miRNAs are observed in some(Cha et al., 2009,Chaudhari et al.,2010).Both induction and repression of some miRNA were seen in different cell types and results are inconclusive (Cha et al.,2009;Chaudhary et al 201; Chaudhary et al 2012; Chaudhary et al 2013;Kwon et al.,2013;Mueller et al.,2013;Shin et al.,2009;Sokolov et al.,2012;Wagner et al.,2010; Kraemer et al., 2011; Moskwa et al.,2011;Niemoeller et al.,2011;Sokolov et al., 2012;Wagner et al.,2010).This inconsistency could be due to different doses of stressor.
DNA damage response influences miRNA expression, at the same time miRNA can also influence DDR, cell cycle etc.The miR-34 family produces a cell-cycle arrest in the G1 phase and slows cell-cycle progression by targeting multiple cell cycle regulators when ectopically produced, implying tumor-suppressing potential. The miR-34 family, for example, specifically targets and inhibits cyclin-dependent kinase 4 (CDK4), CDK6, E2F3, Myc, and NMYC (Chang et al.,2007,He et al., 2007).
MiRNA expression can be influenced by DNA damage and mutation, but miRNA can also regulate DNA damage response and cell cycle.By suppressing the transcripts of numerous genes that govern cell-cycle checkpoints or metabolism, these p53-induced miRNAs contribute to cell-cycle arrest (Su et al.,2010;Georges et al.,2008;Hermeking et al.,2012;Klein et al., 2010; Liu et al.,2011; Suh et al.,2011). Wip1 phosphatase, a master inhibitor in the DDR that inhibits the activation and stability of p53, is targeted and repressed by miR-16 and miR-29, resulting in p53 induction (Ugalde et al.,2011; Zhang et al.,2010). Cellcycle arrest is induced by ectopic expression of miR-192/215, which targets a number of genes that regulate the G1/S and G2/M checkpoints (Bulavin et al.,2004).
The oncogene c-Myc is directly targeted by miR-145, implying that p53 suppresses cMyc activities through regulating miRNA expression (Sachdeva et al.,2009, Suh et al.,2011). p53-induced miRNAs, interestingly, influence p53 activity in a positive feedback loop (Han et al.,2012, Hermeking et al.,2012). SIRT1 acetylation and activation are increased when miR-34 inhibits it (Yamakuchi et al., 2008). Mdm2 expression is directly inhibited by miR-192, miR-194, miR-215, and MiR-605, while Wip1 is inhibited by miR-29, resulting in higher p53 levels and activity. (Braun et al.,2008, Pichiorri et al.,2010, Xiao et al., 2011).
Known modulating factors
miRNA expression profiles are influenced by a variety of DNA damaging stressors. Pothof et al. were the first to notice differences in miRNA expression in cell-cycle checkpoints and DNA repair in UV-treated cells (Pothof et al., 2009). Other DNA damaging agents, such as cisplatin, doxorubicin, IR, and NCS, were used to examine miRNA expression profiles in cells (Galluzzi et al., 2010, Saleh et al.,2011;Suzuki et al.,2009). Different levels of DNA damage appear to activate different groups of miRNAs, implying that miRNAs regulate the DDR through a mechanism that is dependent on the type and severity of the DNA damage.
Quantitative Understanding of the Linkage
The below table gives the evidence for DNA damage responses influencing the expression of miRNA as well as miRNA expression influencing DNA damage response.
Method/ measurement reference |
Reliability |
Strength of evidence |
Assay fit for purpose |
Repeatability/ reproducibility |
Direct measure |
|
Human cell line |
Western blotting,clonal survival assay, FACs(Jaarsveld et al., 2014) |
YEs |
Strong |
Yes |
Yes |
Yes |
Mice |
Free radic CyQuant cell Proliferation assay (Abdelfattah et al.,2018) |
Yes |
Strong |
Yes |
Yes |
Yes |
RNA sequence analysis, Immuno staining, immunoblotting, Flowcytometry, COMET assay, qRT PCR(Liu et al., 2017) |
Yes |
Strong |
Yes |
Yes |
Yes |
|
Microarray (Zhang et al.,2011) |
Yes |
Strong |
Yes |
Yes |
Yes |
|
qRT-PCR, RIP assay, Immunogold EM(Wan et al.,2013) |
Yes |
|||||
Canine |
micro array(Bulkowska et al., 2017) |
Yes |
Strong |
Yes |
Yes |
Yes |
Response-response Relationship
Activity of pri-miR-218, pri-miR-16-1, pri-miR-21, and pri- miR-199a had significantly increased binding with Drosha (2.5- to 3.2-fold) after DNA damage (Zhang et al.,2011)
Time-scale
It has been noted that, within hours of DNA damage,miRNA expression were induced(Wan et al.,2013).
Known Feedforward/Feedback loops influencing this KER
Not specific ones available.
Domain of Applicability
Not specific through any particular life stage or gender.
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.
Braun, C. J., Zhang, X., Savelyeva, I., Wolff, S., Moll, U. M., Schepeler, T., ... & Dobbelstein, M. (2008). p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest. Cancer research, 68(24), 10094-10104.
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.
Bulavin, D. V., Phillips, C., Nannenga, B., Timofeev, O., Donehower, L. A., Anderson, C. W., ... & Fornace, A. J. (2004). Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16 Ink4a-p19 Arf pathway. Nature genetics, 36(4), 343-350.
Cha, H. J., Shin, S., Yoo, H., Lee, E. M., Bae, S., Yang, K. H., ... & An, S. (2009). Identification of ionizing radiation-responsive microRNAs in the IM9 human B lymphoblastic cell line. International journal of oncology, 34(6), 1661-1668.
Chaudhry, M. A., & Omaruddin, R. A. (2012). Differential regulation of microRNA expression in irradiated and bystander cells. Molecular Biology, 46(4), 569-578.
Chaudhry, M. A., Omaruddin, R. A., Brumbaugh, C. D., Tariq, M. A., & Pourmand, N. (2013). Identification of radiation-induced microRNA transcriptome by next-generation massively parallel sequencing. Journal of radiation research, 54(5), 808-822..
Chaudhry, M. A., Omaruddin, R. A., Kreger, B., De Toledo, S. M., & Azzam, E. I. (2012). Micro RNA responses to chronic or acute exposures to low dose ionizing radiation. Molecular biology reports, 39(7), 7549-7558.
Chaudhry, M. A., Sachdeva, H., & Omaruddin, R. A. (2010). Radiation-induced micro-RNA modulation in glioblastoma cells differing in DNA-repair pathways. DNA and cell biology, 29(9), 553-561..
Chang, T. C., Wentzel, E. A., Kent, O. A., Ramachandran, K., Mullendore, M., Lee, K. H., ... & Mendell, J. T. (2007). Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular cell, 26(5), 745-752.
Galluzzi, L., Morselli, E., Vitale, I., Kepp, O., Senovilla, L., Criollo, A., ... & Kroemer, G. (2010). miR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer research, 70(5), 1793-1803.
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., 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.
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.
Hermeking, H. (2012). MicroRNAs in the p53 network: micromanagement of tumour suppression. Nature reviews cancer, 12(9), 613-626.
He, L., He, X., Lim, L. P., De Stanchina, E., Xuan, Z., Liang, Y., ... & Hannon, G. J. (2007). A microRNA component of the p53 tumour suppressor network. Nature, 447(7148), 1130-1134.
Kim, J. W., Mori, S., & Nevins, J. R. (2010). Myc-induced microRNAs integrate Myc-mediated cell proliferation and cell fate. Cancer research, 70(12), 4820-4828.
Klein, U., Lia, M., Crespo, M., Siegel, R., Shen, Q., Mo, T., ... & Dalla-Favera, R. (2010). The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer cell, 17(1), 28-40.
Kraemer, A., Anastasov, N., Angermeier, M., Winkler, K., Atkinson, M. J., & Moertl, S. (2011). MicroRNA-mediated processes are essential for the cellular radiation response. Radiation research, 176(5), 575-586.
Kwon, J. E., Kim, B. Y., Kwak, S. Y., Bae, I. H., & Han, Y. H. (2013). Ionizing radiation-inducible microRNA miR-193a-3p induces apoptosis by directly targeting Mcl-1. Apoptosis, 18(7), 896-909.
Liu, M., Lang, N., Chen, X., Tang, Q., Liu, S., Huang, J., ... & Bi, F. (2011). miR-185 targets RhoA and Cdc42 expression and inhibits the proliferation potential of human colorectal cells. Cancer letters, 301(2), 151-160.
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.
Meek, D. W. (2009). Tumour suppression by p53: a role for the DNA damage response?. Nature Reviews Cancer, 9(10), 714-723.
Moskwa, P., Buffa, F. M., Pan, Y., Panchakshari, R., Gottipati, P., Muschel, R. J., ... & Chowdhury, D. (2011). miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Molecular cell, 41(2), 210-220.
Mueller, A. C., Sun, D., & Dutta, A. (2013). The miR-99 family regulates the DNA damage response through its target SNF2H. Oncogene, 32(9), 1164-1172.
Niemoeller, O. M., Niyazi, M., Corradini, S., Zehentmayr, F., Li, M., Lauber, K., & Belka, C. (2011). MicroRNA expression profiles in human cancer cells after ionizing radiation. Radiation oncology, 6(1), 1-5.
Pichiorri, F., Suh, S. S., Rocci, A., De Luca, L., Taccioli, C., Santhanam, R., ... & Croce, C. M. (2010). Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer cell, 18(4), 367-381.
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.
Riaz, M., van Jaarsveld, M. T., Hollestelle, A., Prager-van der Smissen, W. J., Heine, A. A., Boersma, A. W., ... & Martens, J. W. (2013). miRNA expression profiling of 51 human breast cancer cell lines reveals subtype and driver mutation-specific miRNAs. Breast cancer research, 15(2), 1-17.
Shin, S., Cha, H. J., Lee, E. M., Lee, S. J., Seo, S. K., Jin, H. O., ... & An, S. (2009). Alteration of miRNA profiles by ionizing radiation in A549 human non-small cell lung cancer cells. International journal of oncology, 35(1), 81-86.
Sokolov, M. V., Panyutin, I. V., & Neumann, R. D. (2012). Unraveling the global microRNAome responses to ionizing radiation in human embryonic stem cells. PloS one, 7(2), e31028.
Su, X., Chakravarti, D., Cho, M. S., Liu, L., Gi, Y. J., Lin, Y. L., ... & Flores, E. R. (2010). TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature, 467(7318), 986-990.
Suh, S. O., Chen, Y., Zaman, M. S., Hirata, H., Yamamura, S., Shahryari, V., ... & Dahiya, R. (2011). MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. Carcinogenesis, 32(5), 772-778.
Sachdeva, M., Zhu, S., Wu, F., Wu, H., Walia, V., Kumar, S., ... & Mo, Y. Y. (2009). p53 represses c-Myc through induction of the tumor suppressor miR-145. Proceedings of the National Academy of Sciences, 106(9), 3207-3212.
Suh, S. O., Chen, Y., Zaman, M. S., Hirata, H., Yamamura, S., Shahryari, V., ... & Dahiya, R. (2011). MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. Carcinogenesis, 32(5), 772-778.
Saleh, A. D., Savage, J. E., Cao, L., Soule, B. P., Ly, D., DeGraff, W., ... & Simone, N. L. (2011). Cellular stress induced alterations in microRNA let-7a and let-7b expression are dependent on p53. PloS one, 6(10), e24429.
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.
Ugalde, A. P., Ramsay, A. J., De La Rosa, J., Varela, I., Mariño, G., Cadiñanos, J., ... & López‐Otín, C. (2011). Aging and chronic DNA damage response activate a regulatory pathway involving miR‐29 and p53. The EMBO journal, 30(11), 2219-2232.
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 der Auwera, I., Limame, R., Van Dam, P., Vermeulen, P. B., Dirix, L. Y., & Van Laere, S. J. (2010). Integrated miRNA and mRNA expression profiling of the inflammatory breast cancer subtype. British journal of cancer, 103(4), 532-541.
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.
Wagner-Ecker, M., Schwager, C., Wirkner, U., Abdollahi, A., & Huber, P. E. (2010). MicroRNA expression after ionizing radiation in human endothelial cells. Radiation oncology, 5(1), 1-10.
Xiao, J., Lin, H., Luo, X., Luo, X., & Wang, Z. (2011). miR‐605 joins p53 network to form a p53: miR‐605: Mdm2 positive feedback loop in response to stress. The EMBO journal, 30(3), 524-532.
Yamakuchi, M., Ferlito, M., & Lowenstein, C. J. (2008). miR-34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences, 105(36), 13421-13426.
Yan, H. L., Xue, G., Mei, Q., Wang, Y. Z., Ding, F. X., Liu, M. F., ... & Sun, S. H. (2009). Repression of the miR‐17‐92 cluster by p53 has an important function in hypoxia‐induced apoptosis. The EMBO journal, 28(18), 2719-2732.
Zhang, X., Wan, G., Mlotshwa, S., Vance, V., Berger, F. G., Chen, H., & Lu, X. (2010). Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway. Cancer research, 70(18), 7176-7186.
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.