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

Abstract

The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different types of lesions occurring in DNA, double-strand breaks (DSBs) are considered the most harmful type of lesion, which can result in significant loss of genetic information, leading to diseases, such as cancer. DSB repair occurs through two main mechanisms, called non-homologous end joining (NHEJ) and homologous recombination repair (HRR). There is evidence showing that miRNAs play an important role in the regulation of genes acting in NHEJ and HRR mechanisms, either through direct complementary binding to mRNA targets, thus, repressing translation, or by targeting other genes involved in the transcription and activity of DSB repair genes. Therefore, alteration of miRNA expression has an impact on the ability of cells to repair DSBs, which, in turn, affects cancer therapy sensitivity. This latter gives account of the importance of miRNAs as regulators of NHEJ and HRR and places them as a promising target to improve cancer therapy. Here, we review recent reports demonstrating an association between miRNAs and genes involved in NHEJ and HRR. We employed the Web of Science search query TS ("gene official symbol/gene aliases*" AND "miRNA/microRNA/miR-") and focused on articles published in the last decade, between 2010 and 2021. We also performed a data analysis to represent miRNA-mRNA validated interactions from TarBase v.8, in order to offer an updated overview about the role of miRNAs as regulators of DSB repair.

Keywords: DNA repair; double-strand breaks; homologous recombination repair; miRNAs; non-homologous end joining.

Figure 1

Human miRNA–mRNA-validated interactions involving NHEJ genes according to a data analysis from TarBase v.8 interactions database. There are 275 miRNAs and 358 interactions represented. Graphic created using circlize R package [17].

Figure 2

Human miRNA–mRNA interactions involving HRR genes according to a data analysis from TarBase v.8 interactions database. There are 210 miRNAs and 362 interactions represented. Graphic created using circlize R package [17].

Figure 3

General mechanism for repairing DSBs through NHEJ and miRNAs reported to directly or indirectly modulate gene expression of various NHEJ genes. The NHEJ repair mechanism is presented in stages. DNA complex formation stage, of each Ku protein, value in parentheses refers to the number of miRNA–mRNA interactions validated according to the analysis of the TarBase v.8 interactions database, in the same way for the entire figure. The recruitment of DNA-PKcs and the DSB signaling step show the interactions of PRKDC and miRNAs. In the End resection and generation of microhomology regions stage, the number of validated interactions for Pol μ, Pol λ and Artemis is shown. Finally, for the End ligation stage, the specific interactions between XRCC4, XLF and LIG4 are shown through the lines.

Figure 4

Mechanism of DSB repair by HRR and the miRNAs involved in direct or indirect regulation of some HRR gene expression. The HRR mechanism is represented by stages, the value in parenthesis refers to the number of miRNA–mRNA interactions according to analysis from TarBase v.8 interaction database. In the DSB detection, resection initiation and signaling stage show interactions for MRE11, RAD50, NBS1, and CtIP. Resection extension stage shows interactions of RPA, BRCA1, BLM and EXO1. In homolog strand exchange and DNA synthesis stage is shown miRNA interactions with RAD51, BRCA2 and POLD. Finally for the Strand ligation stage is shown the interaction between LIG1 and miR-874.