ADAR1 protein offers a potential therapeutic target for cancer

A research team from The Wistar Institute has discovered a new role of ADAR1—a protein that plays a key role in RNA editing—and found that the ADAR1p110 isoform controls genome stability at the ends of chromosomes and is needed for the continued spread of cancer cells.

ADAR1 protein offers a potential therapeutic target for cancer
Dr Kazuko Nishikura. Image Credit: The Wistar Institute.

These results, published in the Nature Communications journal, demonstrate an additional oncogenic role of the ADAR1 protein and reconfirm its viability as a therapeutic target in cancer.

The laboratory of Kazuko Nishikura, Ph.D., a professor in the Gene Expression & Regulation program of the Wistar Institute Cancer Center, was one among the first to identify the ADAR1 protein in mammalian cells and to define the mechanism of RNA editing and its various functions in the cell.

Just like how one or more letters are changed in a written word, RNA editing enables cells to make discrete changes to single nucleotides inside the RNA molecule. This mechanism can influence the metabolism of RNA and how it is converted into proteins. It also holds implications for antitumor immunity and developmental and neurological disorders.

ADAR1p110 and ADAR1p150 are two types of ADAR1 proteins. While the RNA editing function of the latter protein, situated in the cytoplasm, has been widely designed, the role of the nuclear ADAR1p110 isoform continued to be elusive.

We discovered that in the nucleus, ADAR1p110 oversees a similar mechanism to ADAR1p150, the better-known cytoplasmic variant, but the editing process in this case targets particular nucleic acid structures called R-loops when formed at the chromosome ends. Through this function, ADAR1p110 seems to be essential for cancer cell proliferation.”

Kazuko Nishikura, PhD, Professor, Gene Expression & Regulation Program, The Wistar Institute Cancer Center

R-loops are formed during gene transcription when the newly produced RNA remains fixed to it rather than disassociating from its template DNA strand, thus resulting in a stable DNA/RNA hybrid.

Although such structures may be advantageous for transcriptional regulation in specific circumstances, the build-up of R-loops can cause genomic instability, DNA damage, and chromosome rearrangement and is associated with cancer and neurological disorders.

Nishikura and collaborators discovered that the ADAR1p110 protein allows the cells to overcome R-loops and inhibit their accumulation by modifying both the RNA and DNA strands involved in the structure and promoting the degradation of the RNA strand through the RNA H2 enzyme.

Most importantly, the team found that the depletion of the ADAR1p110 protein leads to the build-up of R-loops at the ends of the chromosomes, suggesting that the ADAR1p110 protein acts on R-loops produced in telomeric regions and is needed to maintain the stability of telomeres.

Telomeres act as an internal clock that informs normal cells when it is time to cease proliferating. Similar to the plastic coating on the tips of the shoelaces, the telomeres shield the ends of the chromosomes against the loss of genetic material at each division of cells, and their progressive shortening gradually causes cell death or growth arrest.

Tumor cells bypass this process to become immortal. The team has also found that the depletion of the ADAR1p110 protein leads to widespread telomeric DNA damage and stops the proliferation, particularly in cancer cells.

It has recently been suggested ADAR1 inhibitors could potentiate tumor response to immunotherapy by interfering with certain cytoplasmic ADAR1p150 function. Based on our findings on the role of nuclear ADAR1p110 in maintaining telomere stability in cancer cells, we predict that ADAR1 inhibitors would be very effective anticancer therapeutics by interfering with two different and independent pro-oncogenic ADAR1functions exerted by the two isoforms.”

Kazuko Nishikura, PhD, Professor, Gene Expression & Regulation Program, The Wistar Institute Cancer Center

Source:
Journal reference:

Shiromoto, Y., et al. (2021) ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells. Nature Communications. doi.org/10.1038/s41467-021-21921-x.

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