Interactions between miRNAs and Double-Strand Breaks DNA Repair Genes, Pursuing a Fine-Tuning of Repair

Peraza-Vega, Ricardo I.; Valverde, Mahara; Rojas, Emilio

doi:10.3390/ijms23063231

Cited by 10 publications

(10 citation statements)

References 125 publications

(151 reference statements)

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“…Notably, multiple miRNAs remained downregulated at day 7 after 8 Gy irradiation in BALB/c, whereas C3H/HeJ mice showed a return to baseline expression by this timepoint. While miR-148a, -148b, -183, -210, and let-7a are negatively associated with homologous recombination and their upregulation leads to downregulation of DNA-repair genes BRCA1/2, RAD50, and RAD51 [55]. This is an interesting result considering we see upregulation of several of these miRNAs in BALB/c samples.…”

Section: Discussionsupporting

confidence: 52%

Comparative Analysis of miRNA Expression after Whole-Body Irradiation Across Three Strains of Mice

Martello,

Bylicky,

Shankavaram

et al. 2023

Radiation Research

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Whole- or partial-body exposure to ionizing radiation damages major organ systems, leading to dysfunction on both acute and chronic timescales. Radiation medical countermeasures can mitigate acute damages and may delay chronic effects when delivered within days after exposure. However, in the event of widespread radiation exposure, there will inevitably be scarce resources with limited countermeasures to distribute among the affected population. Radiation biodosimetry is necessary to separate exposed from unexposed victims and determine those who requires the most urgent care. Blood-based, microRNA signatures have great potential for biodosimetry, but the affected population in such a situation will be genetically heterogeneous and have varying miRNA responses to radiation. Thus, there is a need to understand differences in radiation-induced miRNA expression across different genetic backgrounds to develop a robust signature. We used inbred mouse strains C3H/HeJ and BALB/c mice to determine how accurate miRNA in blood would be in developing markers for radiation vs. no radiation, low dose (1 Gy, 2 Gy) vs. high dose (4 Gy, 8 Gy), and high risk (8 Gy) vs. low risk (1 Gy, 2 Gy, 4 Gy). Mice were exposed to whole-body doses of 0 Gy, 1 Gy, 2 Gy, 4 Gy, or 8 Gy of X rays. MiRNA expression changes were identified using NanoString nCounter panels on blood RNA collected 1, 2, 3 or 7 days postirradiation. Overall, C3H/HeJ mice had more differentially expressed miRNAs across all doses and timepoints than BALB/c mice. The highest amount of differential expression occurred at days 2 and 3 postirradiation for both strains. Comparison of C3H/HeJ and BALB/c expression profiles to those previously identified in C57BL/6 mice revealed 12 miRNAs that were commonly expressed across all three strains, only one of which, miR-340-5p, displayed a consistent regulation pattern in all three miRNA data. Notably multiple Let-7 family members predicted high-dose and high-risk radiation exposure (Let-7a, Let-7f, Let-7e, Let-7g, and Let-7d). KEGG pathway analysis demonstrated involvement of these predicted miRNAs in pathways related to: Fatty acid metabolism, Lysine degradation and FoxO signaling. These findings indicate differences in the miRNA response to radiation across various genetic backgrounds, and highlights key similarities, which we exploited to discover miRNAs that predict radiation exposure. Our study demonstrates the need and the utility of including multiple animal strains in developing and validating biodosimetry diagnostic signatures. From this data, we developed highly accurate miRNA signatures capable of predicting exposed and unexposed subjects within a genetically heterogeneous population as quickly as 24 h of exposure to radiation.

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Section: Discussionsupporting

confidence: 52%

Comparative Analysis of miRNA Expression after Whole-Body Irradiation Across Three Strains of Mice

Martello,

Bylicky,

Shankavaram

et al. 2023

Radiation Research

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“…3 ): the HRR, NHEJ, base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), translesion DNA synthesis (TLS), and Fanconi anemia (FA) pathways. Interactions among the DNA damage response, DNA repair components and miRNAs have been reported [ 39 ]. The ectopic expression of miRNAs, as regulatory factors, can interfere with the activity of DNA repair mechanisms, which have been implicated in multiple types of resistance [ 40 ].…”

Section: Mechanisms Of Drug Resistance In Ovarian Cancermentioning

confidence: 99%

Drug resistance in ovarian cancer: from mechanism to clinical trial

Wang,

Zhu

et al. 2024

Mol Cancer

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Ovarian cancer is the leading cause of gynecological cancer-related death. Drug resistance is the bottleneck in ovarian cancer treatment. The increasing use of novel drugs in clinical practice poses challenges for the treatment of drug-resistant ovarian cancer. Continuing to classify drug resistance according to drug type without understanding the underlying mechanisms is unsuitable for current clinical practice. We reviewed the literature regarding various drug resistance mechanisms in ovarian cancer and found that the main resistance mechanisms are as follows: abnormalities in transmembrane transport, alterations in DNA damage repair, dysregulation of cancer-associated signaling pathways, and epigenetic modifications. DNA methylation, histone modifications and noncoding RNA activity, three key classes of epigenetic modifications, constitute pivotal mechanisms of drug resistance. One drug can have multiple resistance mechanisms. Moreover, common chemotherapies and targeted drugs may have cross (overlapping) resistance mechanisms. MicroRNAs (miRNAs) can interfere with and thus regulate the abovementioned pathways. A subclass of miRNAs, “epi-miRNAs”, can modulate epigenetic regulators to impact therapeutic responses. Thus, we also reviewed the regulatory influence of miRNAs on resistance mechanisms. Moreover, we summarized recent phase I/II clinical trials of novel drugs for ovarian cancer based on the abovementioned resistance mechanisms. A multitude of new therapies are under evaluation, and the preliminary results are encouraging. This review provides new insight into the classification of drug resistance mechanisms in ovarian cancer and may facilitate in the successful treatment of resistant ovarian cancer.

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“…MicroRNAs (miRNA) are key post-transcriptional regulators of gene expression that are also involved in DNA repair pathways (for review see (10)) pursuing a fine-tuning of repair and also contribute to TMZ resistance processes. However, their role in TMZ resistance has not been systematically analyzed.…”

Section: Introductionmentioning

confidence: 99%

Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex

Kashani

Hlavačková

Haemmig

et al. 2023

Preprint

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Despite standard of care, glioblastoma IDH wt (GBM) inevitably recur accentuating the need to elucidate mechanisms of therapy resistance. The DNA alkylating agent temozolomide (TMZ) triggers futile DNA mismatch repair cycles and persistent DNA double strand breaks, but tumors counteract this genotoxic stress by inducing DNA damage repair and survival pathways. GBM cells overexpressing miR-19b-3p were reproducibly selected by TMZ treatment in systematic lentiviral microRNA screens, a finding that was investigated mechanistically. Attenuation of miR-19b in glioblastoma cell lines and primary glioblastoma stem cells (GSCs) induced DNA damage as indicated by enhanced CHK1 and CHK2 phosphorylation, gH2AX foci formation, and senescence. These phenotypes were further enhanced by TMZ treatment. Enhanced expression of miR-19b in GBM tissues was associated with downregulation of regulatory subunit PPP2R5E of Ser/Thr phosphatase PP2A in the mesenchymal subtype of GBM in agreement with miR-19b targeting PPP2R5E. Knocking down PPP2R5E antagonized the phenotypes elicited by miR-19b attenuation, and these effects were reversed in miR-19b attenuated/PPP2R5E knockdown cells suggesting a role of the miR-19b/PPP2R5E axis in TMZ-induced DNA damage response. In agreement with PP2A reactivation by miR-19b attenuation, PP2A activating drug, FTY720, or knocking down endogenous PP2A inhibiting proteins (PAIP), acted synergistically with TMZ to induce cell death. Enhanced TMZ resistance elicited by knocking down PPP2R5E was confirmed in orthotopic mouse GSC xenografts. These results provide insights in TMZ resistance mechanisms of GBM elicited by PPP2R5E targeting of miR-19b. Attenuation of miR-19b or PPP2R5E expression could potentially be exploited in adjuvant therapy of GBM.

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Interactions between miRNAs and Double-Strand Breaks DNA Repair Genes, Pursuing a Fine-Tuning of Repair

Cited by 10 publications

References 125 publications

Comparative Analysis of miRNA Expression after Whole-Body Irradiation Across Three Strains of Mice

Comparative Analysis of miRNA Expression after Whole-Body Irradiation Across Three Strains of Mice

Drug resistance in ovarian cancer: from mechanism to clinical trial

Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex

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