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      LncRNA lnc-RI regulates homologous recombination repair of DNA double-strand breaks by stabilizing RAD51 mRNA as a competitive endogenous RNA

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          Abstract

          DNA double-strand break (DSB) repair is critical for the maintenance of genome stability. The current models of the mechanism of DSB repair are based on studies of DNA repair proteins. Long non-coding RNAs (lncRNAs) have recently emerged as new regulatory molecules, with diverse functions in biological processes. In the present study, we found that expression of the ionizing radiation-inducible lncRNA, lnc-RI, was correlate negatively with micronucleus frequencies in human peripheral blood lymphocytes. Knockdown of lnc-RI significantly increased spontaneous DSBs levels, which was confirmed to be associated with the decreased efficiency of homologous recombination (HR) repair of DSBs. The expression of RAD51, a key recombinase in the HR pathway, decreased sharply in lnc-RI-depressed cells. In a further investigation, we demonstrated that miR-193a-3p could bind with both lnc-RI and RAD51 mRNA and depressed the expression of lnc-RI and RAD51 mRNA. Lnc-RI acted as a competitive endogenous RNA (ceRNA) to stabilize RAD51 mRNA via competitive binding with miR-193a-3p and release of its inhibition of RAD51 expression. To our knowledge, this is the first study to demonstrate the role of lnc-RI in regulating HR repair of DSBs. The feedback loop established in the current study suggests that lnc-RI is critical for the maintenance of genomic stability.

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          Most cited references 26

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          Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein.

          The RAD51 gene of S. cerevisiae is involved in mitotic recombination and repair of DNA damage and also in meiosis. We show that the rad51 null mutant accumulates meiosis-specific double-strand breaks (DSBs) at a recombination hotspot and reduces the formation of physical recombinants. Rad51 protein shows structural similarity to RecA protein, the bacterial strand exchange protein. Furthermore, we have found that Rad51 protein is similar to RecA in its DNA binding properties and binds directly to Rad52 protein, which also plays a crucial role in recombination. These results suggest that the Rad51 protein, probably together with Rad52 protein, is involved in a step to convert DSBs to the next intermediate in recombination. Rad51 protein is also homologous to a meiosis-specific Dmc1 protein of S. cerevisiae.
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            Homologous recombination and its regulation

            Homologous recombination (HR) is critical both for repairing DNA lesions in mitosis and for chromosomal pairing and exchange during meiosis. However, some forms of HR can also lead to undesirable DNA rearrangements. Multiple regulatory mechanisms have evolved to ensure that HR takes place at the right time, place and manner. Several of these impinge on the control of Rad51 nucleofilaments that play a central role in HR. Some factors promote the formation of these structures while others lead to their disassembly or the use of alternative repair pathways. In this article, we review these mechanisms in both mitotic and meiotic environments and in different eukaryotic taxa, with an emphasis on yeast and mammal systems. Since mutations in several proteins that regulate Rad51 nucleofilaments are associated with cancer and cancer-prone syndromes, we discuss how understanding their functions can lead to the development of better tools for cancer diagnosis and therapy.
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              CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation.

              Abnormal mitochondrial fission participates in the pathogenesis of many diseases. Long non-coding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the regulation of mitochondrial network is unclear. Here we report that a lncRNA, named cardiac apoptosis-related lncRNA (CARL), can suppress mitochondrial fission and apoptosis by targeting miR-539 and PHB2. The results show that PHB2 is able to inhibit mitochondrial fission and apoptosis. miR-539 is responsible for the dysfunction of PHB2 and regulates mitochondrial fission and apoptosis by targeting PHB2. Further, we show that CARL can act as an endogenous miR-539 sponge that regulates PHB2 expression, mitochondrial fission and apoptosis. Our present study reveals a model of mitochondrial fission regulation that is composed of CARL, miR-539 and PHB2. Modulation of their levels may provide a new approach for tackling apoptosis and myocardial infarction.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                25 January 2018
                04 December 2017
                04 December 2017
                : 46
                : 2
                : 717-729
                Affiliations
                [1 ]School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu 215123, PR China
                [2 ]Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China
                Author notes
                To whom correspondence should be addressed. Tel: +86 10 66930248; Fax: +86 10 68183899; Email: wangzhidong_1977@ 123456aliyun.com . Correspondence may also be addressed to Pingkun Zhou. Tel: +86 10 66931217; Fax: +86 10 68183899; Email: zhoupk@ 123456bmi.ac.cn
                Article
                gkx1224
                10.1093/nar/gkx1224
                5778505
                29216366
                © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                Page count
                Pages: 13
                Product
                Categories
                Genome Integrity, Repair and Replication

                Genetics

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