CircRNA inhibits DNA damage repair by interacting with host gene

Abstract

Background: Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. Method: We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. Results: We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. Conclusion: Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

Novel role of circRSU1 in the progression of osteoarthritis by adjusting oxidative stress

“…Given the cytoplasmic localization and exonic formation of circRSU1, as well as the opposite expression trend of circRSU1 and linear mRSU1 under IL-1β and H 2 O 2 stimulation, we hypothesized the presence of a mechanism that regulates their biogenesis. Xu et al 86 reported that circSMARCA5 can form an R-loop at its parent gene locus, which results in transcriptional pausing of SMARCA5 and leads to the upregulated circSMARCA5 and downregulated mSMARCA5 in breast cancer. Zhang et al 87 also reported a mechanism for the selection of RNA pairing across flanking introns or within a single individual intron that leads to competition between the back-splicing of circRNAs and the canonical splicing of linear mRNAs.…”

Cancer-related circular RNA: diverse biological functions

“…In addition, hsa_circ_0025202 could absorb miR-182-5p to regulate the expression and activity of FOXO3a and then affect tumor inhibition and tamoxifen sensitization effects, indicating that hsa_circ_0025202 could be a therapeutic target in patients with HR-positive BC, especially in those receiving TAM therapy. In contrast to its host gene SMARCA5, circSMARCA5 is reduced in breast cancer tissues [ 74 ]. The enforced expression of circSMARCA5 could induce drug sensitivity in breast cancer cell lines in vitro and in vivo.…”

CircMETTL3, Upregulated in a m6A-dependent Manner, Promotes Breast Cancer Progression through circMETTL3/miR-31-5p/CDK1 axis

“…circKIAA1429 accelerated hepatocellular carcinoma advancement through enhancing ZEB1 mRNA stability [26]. circSMARCA5 terminated the transcription of SMARCA5 to inhibit DNA damage repair [14]. circSHPRH suppressed glioma tumorigenesis by encoding a novel protein [36].…”

“…Previous studies showed circRNAs might act as a sponge to increase its host gene expression [39][40][41] or decrease the parental gene expression by terminating the transcription of the parental gene [14]. However, the relation of circMETTL3 and its parental gene, METTL3, was still elusive.…”