MiR-34s negatively regulate homologous recombination through targeting RAD51

Chen, Shuangjing; Liu, Ruixue; Wang, Qi; Qi, Zhenhua; Hu, Yingchun; Zhou, Pingkun; Wang, Zhidong

doi:10.1016/j.abb.2019.03.017

Cited by 19 publications

(12 citation statements)

References 45 publications

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“…Accumulating evidence has suggested that miRNAs actively take part in the regulation of the DNA damage/repair network by affecting the expression of DNA repair genes such as RAD51, ultimately regulating their biological functions [36,37] . Polymorphisms in the predicted miRNA target sites of these genes have been shown to be strongly involved in regulating the expression of the mRNAs, either by providing mutated binding sites which alter miRNA-mRNA interactions, or by forming hairpin loop structures which stabilize and thus slow down mRNA degradation [38,39] .…”

Section: Discussionmentioning

confidence: 99%

A functional variant in the RAD51 3′ UTR is associated with survival of hepatocellular carcinoma patients

Qiu

Liu

Lin

et al. 2020

Preprint

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The RAD51 gene plays an important role in DNA repair by homologous recombination, and is involved in the development and progression of multiple cancers. While single nucleotide polymorphisms in RAD51 have been previously described to impact patient prognosis, it is still unclear whether this is also true for hepatocellular carcinoma (HCC). This study therefore aimed to identify genetic variants in RAD51 and determine the effect of these variants on the survival of patients with HCC. In this study, we performed genotyping assays for RAD51 polymorphisms in a cohort of 368 patients with HCC who had undergone radical surgery resection. Using multivariate cox proportional hazards model and Kaplan-Meier analyses with log-rank tests, we compared the survival of patients with HCC according to RAD51 SNP genotypes. We performed expression quantitative trait loci (eQTL) analysis to investigate correlations between SNP rs12593359 and RAD51 mRNA expression levels from the genotype-tissue expression portal. We identified one potential functional variant, rs12593359, located in a microRNA (miRNA) binding site in the RAD51 3′ untranslated region, to be an independent predictor of overall survival of patients with HCC in the dominant model. Patients carrying GT/TT genotypes had a significantly increased risk of death when compared with those carrying GG genotype (adjusted hazard ratio = 1.34, 95% confidence interval = 1.02–1.76, P = 0.035). Kaplan-Meier curve analysis showed a markedly shorter survival time for patients with HCC carrying GT/TT genotypes of SNP rs12593359 (19.0 months vs. 36.0 months; P log−rank = 0.012). Notably, this effect was particularly pronounced in several subgroups of patients (e.g., males, Hepatitis B virus-positive patients, patients with a single tumor nodule, patients with alpha-fetoprotein (AFP) < 400 ng/ml, or patients who were cancer embolus-free). Additional expression analysis of quantitative trait loci showed that the rs12593359 was significantly associated with RAD51 mRNA expression levels in 483 cell-cultured fibroblasts (P = 1.1 × 10− 4). These findings provide evidence that RAD51 rs12593359 is associated with HCC survival and may serve as a promising predictor of survival in patients with HCC.

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Section: Discussionmentioning

confidence: 99%

A functional variant in the RAD51 3′ UTR is associated with survival of hepatocellular carcinoma patients

Qiu

Liu

Lin

et al. 2020

Preprint

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“…miR-34a was shown to regulate RAD51 by directly binding to its 3'-UTR, controlling HR and promoting radiosensitivity in NSCLC cells [17]. In addition, miR-155 was reported to regulate DNA repair activity and sensitivity to IR by repressing RAD51 in breast cancer cells [18], and miR-34a/b/c-5p was shown to directly target the RAD51 mRNA 3 -UTR or indirectly inhibit RAD51 expression via the p53 signaling pathway, indicating that miR-34s overexpression reduces the efficiency of HR repair and induces DSBs by down-regulating RAD51 expression [19].…”

Section: Mirnas Involved In the Dna Damage Responsementioning

confidence: 99%

Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA

Chen

Yeh

et al. 2020

IJMS

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Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. For patients who are resistant to monotherapy, multimodal therapy is a basic oncologic principle that incorporates surgery, radiotherapy (RT), and chemotherapy providing survival benefits for patients with most types of cancer. Although liver has low tolerance for radiation, high-precision RT for local HCC minimizes the likelihood of radiation-induced liver disease (RILD) in noncancerous liver tissue. RT have several therapeutic benefits, including the down-staging of tumors to make them resectable and repression of metastasis. The DNA damage response (DDR) is a cellular response to irradiation (IR), including DNA repair of injured cells and induction of programmed cell death, thereby resulting in maintenance of cell homeostasis. Molecules that block the activity of proteins in DDR pathways have been found to enhance radiotherapeutic effects. These molecules include antibodies, kinase inhibitors, siRNAs and miRNAs. MicroRNAs (miRNAs) are short non-coding regulatory RNAs binding to the 3 -untranslated regions (3 -UTR) of the messenger RNAs (mRNAs) of target genes, regulating their translation and expression of proteins. Thus, miRNAs and their target genes constitute complicated interactive networks, which interact with other molecules during carcinogenesis. Due to their promising roles in carcinogenesis, miRNAs were shown to be the potential factors that mediated radiosensitivity and optimized outcomes of the combination of systemic therapy and radiotherapy.

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“…Many recent studies have reported the pivotal role of ncRNAs in DNA repair and genomic rearrangements in different research models (41)(42)(43)(44). There is growing evidence that ncRNAs regulate the DDR, especially small microRNAs (miRNAs), which are induced at DNA-DSBs, thus mediating repair (23,41,45). Regulatory short miRNAs are ncRNAs encoded in intronic regions of proteincoding genes or in the intergenic regions of the genome (23,42).…”

Section: The Underestimated Role Of Small Ncrnas In Dna Damage Response and Repairmentioning

confidence: 99%

Molecular Mechanisms of Specific Cellular DNA Damage Response and Repair Induced by the Mixed Radiation Field During Boron Neutron Capture Therapy

Maliszewska‐Olejniczak

Kaniowski

Araszkiewicz

et al. 2021

Front. Oncol.

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The impact of a mixed neutron-gamma beam on the activation of DNA damage response (DDR) proteins and non-coding RNAs (ncRNAs) is poorly understood. Ionizing radiation is characterized by its biological effectiveness and is related to linear energy transfer (LET). Neutron-gamma mixed beam used in boron neutron capture therapy (BNCT) can induce another type of DNA damage such as clustered DNA or multiple damaged sites, as indicated for high LET particles, such as alpha particles, carbon ions, and protons. We speculate that after exposure to a mixed radiation field, the repair capacity might reduce, leading to unrepaired complex DNA damage for a long period and may promote genome instability and cell death. This review will focus on the poorly studied impact of neutron-gamma mixed beams with an emphasis on DNA damage and molecular mechanisms of repair. In case of BNCT, it is not clear which repair pathway is involved, and recent experimental work will be presented. Further understanding of BNCT-induced DDR mechanisms may lead to improved therapeutic efficiency against different tumors.

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MiR-34s negatively regulate homologous recombination through targeting RAD51

Cited by 19 publications

References 45 publications

A functional variant in the RAD51 3′ UTR is associated with survival of hepatocellular carcinoma patients

A functional variant in the RAD51 3′ UTR is associated with survival of hepatocellular carcinoma patients

Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA

Molecular Mechanisms of Specific Cellular DNA Damage Response and Repair Induced by the Mixed Radiation Field During Boron Neutron Capture Therapy

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