RNA molecules control repair of human DNA in cancer cells

RNA molecules control repair of human DNA in cancer cells
Fig. 1: scaRNA2 localizes at DNA lesions and loss of this RNA leads to accumulation of DNA double-strand breaks and genomic instability. a Schematic structure of scaRNA2, illustrating the GU-rich region, C/D domains and U2 snRNA antisense regions. Binding sites for smFISH probes, qPCR primers, GapmeRs and the MS2 loop insertion site are also shown. b Sub-cellular distribution of scaRNA2 in untreated or irradiated U2OS cells as determined by qPCR. The values shown are means ± SD, n = 3. Unless otherwise indicated, all n = 3 refer to three biologically independent experiments. Ns (not significant) as determined by one-way ANOVA and two-sided Dunnett’s multiple comparisons test. c smRNA FISH of scaRNA2 and immunostaining of the Cajal body marker coilin in U2OS cells expressing scaRNA2 endogenously or overexpressed for 24 h (n = 3). Nuclei were stained with DAPI in all immunofluorescence experiments. d smRNA FISH of scaRNA2 and immunostaining of the DNA damage marker γH2AX in laser micro-irradiated (5 min recovery) U2OS cells overexpressing scaRNA2 for 24 h (n = 3). smRNA FISH for U2 snRNA was performed under the same conditions but without overexpression of scaRNA2. e smFISH of scaRNA2 in U2OS FokI cells transfected with a scaRNA2 plasmid for 24 h and treated with Shield and 4-OHT for an additional 4 h (n = 3). Immunostaining of γH2AX was performed under the same conditions but without overexpression of scaRNA2. f Immunostaining of γH2AX in irradiated (2 Gy, 1 or 24 h recovery) U2OS cells depleted or not of scaRNA2 for 48 h. The graph below shows the percentage of 100–200 cells (means ± SD, n = 3) whose nuclei contained > 10 γH2AX foci, **p < 0.01, ns (not significant) as determined by one-way ANOVA and two-sided Dunnett’s multiple comparisons test. The images depict a representative cell exhibiting the potential change in phenotype. g Immunostaining of γH2AX in untreated or irradiated (2 Gy, 1 or 24 h recovery) U2OS scaRNA2 WT or KO cells. The graph below shows the percentage of 100–200 cells (means ± SD, n = 3) whose nuclei contained more than 10 γH2AX foci, **p < 0.01, ns (not significant) as determined by unpaired two-tailed t-test. h DAPI staining in U2OS scaRNA2 WT or KO cells. The graph below shows the percentage of 100–200 cells (means ± SD, n = 3) that contained a micronucleus (indicated by a white arrowhead in the representative image), **p < 0.01 as determined by unpaired two-tailed t-test. Source data are provided as a Source Data file. Credit:DOI: 10.1038/s41467-022-28646-5

A new study from Karolinska Institutet in Sweden shows how certain RNA molecules control the repair of damaged DNA in cancer cells, a discovery that could eventually give rise to better cancer treatments. The study is published today in the journal Nature Communications.

It was long assumed that RNA molecules—basic molecules that exist in all living organisms—only participated in protein synthesis. New research demonstrates, however, that RNA molecules have a much broader function and can play a key role in the development of disease.

One such disease in , where damage to our cells' DNA can be a contributing factor. DNA damage occurs and is repaired continuously, but in some cases it can lead to carcinogenic mutations in the genome. A fundamental understanding of how our cells repair DNA is therefore key to the design of new treatments.

In this current study, the researchers examined how certain RNA molecules affected the ability of the to repair radiation-damaged or broken DNA strings. They discovered that two molecule types—small Cajal body-specific RNA 2 (scaRNA2) and WRAP53—interacted to regulate the enzyme DNA-dependent protein kinase (DNA-PK), which in turn affected the DNA-repair mechanisms.

Works like an 'on-off' button

"Our findings show that some RNA can bind to an enzyme that repairs damaged DNA and operate like an 'on-off' button for this enzyme, thereby controlling DNA repair," says the study's corresponding author Marianne Farnebo, researcher at the Department of Cell and Molecular Biology and the Department of Biosciences and Nutrition at Karolinska Institutet. "We've also discovered that altered levels of such RNA leads to faulty DNA repair in cancer cells."

The researchers hope that the results can enhance understanding of the part played by RNA in DNA repair and cancer.

"This can open up new approaches to the treatment of cancer, such as using synthetic RNA molecules to stimulate cell death in cancer cells," Marianne Farnebo says.


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More information: Sofie Bergstrand et al, Small Cajal body-associated RNA 2 (scaRNA2) regulates DNA repair pathway choice by inhibiting DNA-PK, Nature Communications (2022). DOI: 10.1038/s41467-022-28646-5
Journal information: Nature Communications

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