Researchers at The Wistar Institute have identified a new function of ADAR1, a protein responsible for RNA editing, discovering that an isoform of this protein regulates genome stability at chromosome ends and is required for continued proliferation of cancer cells.
Adenosine deaminase acting on RNA (ADAR) is the enzyme involved in adenosine-to-inosine RNA editing. In vertebrates, there are three ADAR gene family members – ADAR1, ADAR2 and ADAR3. Researchers have found catalytic enzyme activity in both ADAR1 and ADAR2, but so far, no catalytic activity has been shown in ADAR3. A-to-I editing mainly occurs in noncoding regions that contain repetitive elements Alu and LINE.
Two ADAR1 isoforms, p150 and p110, are generated by the use of separate promoters and alternate splicing. ADAR1p150 mostly localises in the cytoplasm, whereas ADAR1p110 is mostly in the nucleus. The cytoplasmic ADAR1p150 edits 3’UTR double-stranded RNAs and thereby suppresses induction of interferons. Loss of function of this protein underpins the embryonic lethality of Adar1 null mice. It is also involved in the pathogenesis of the severe autoimmune disease Aicardi-Goutières syndrome as well as cancer cell resistance to immune checkpoint blockade. However, the biological functions of the nuclear-localised ADAR1p110 remains largely unknown.
In this study, published in Nature Communications, researchers sought to characterise the editing role of the nuclear-localised ADAR1p110.
The team discovered a key role for the ADAR1p110 isoform in resolving R-loops formed at telomeric repeat regions. R-loops form naturally during gene transcription, but their persistent formation can cause DNA damage and genomic instability and is also linked to neurological disorders and cancer. The researchers found that ADAR1p110 edits both the RNA and the DNA strands of telomeric repeat RNA:DNA hybrids. It is also required for the degradation of RNA strands by the RNase H2 enzyme.
In addition, they found that depletion of the ADAR1p110 isoform led to the accumulation of R-loops at chromosome ends. This indicates that this protein acts on R-loops formed in telomeric regions and is required to preserve telomere stability. The team found that depletion led to extensive telomeric DNA damage and arrested proliferation specifically in cancer cells.
Dr. Kazuko Nishikura, Professor in the Gene Expression & Regulation Program of The Wistar Institute Cancer Center, expressed:
“It has recently been suggested ADAR1 inhibitors could potentiate tumour response to immunotherapy by interfering with certain cytoplasmic ADAR1p150 functions.
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 ADAR1 functions exerted by the two isoforms.”
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