Endogenous reverse transcriptase (ERT)

Endogenous reverse transcriptase (ERT) is an enzyme encoded by endogenous retroelements, primarily Long Interspersed Nuclear Element-1 (LINE-1) and Human Endogenous Retroviruses (HERVs), which constitute nearly 40% of the human genome (Nature, 2017). While usually silenced in healthy somatic cells through epigenetic mechanisms, ERT can become reactivated during aging, cellular stress, or malignancy, leading to the synthesis of complementary DNA (cDNA) from retroelement RNA templates (Cell, 2019). This activity promotes genomic instability through insertional mutagenesis and drives chronic inflammation by activating the cGAS-STING innate immune signaling pathway in response to the accumulation of cytoplasmic DNA (Science, 2014). ERT is increasingly recognized as a therapeutic target in various conditions, including epithelial cancers, autoimmune diseases like Aicardi-Goutières syndrome, and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Frontiers in Genetics, 2020). Pharmacological inhibition of ERT is currently being explored by repurposing nucleoside reverse transcriptase inhibitors (NRTIs), which were originally developed for HIV. These drugs have shown potential in reducing inflammatory markers and slowing disease progression in clinical and preclinical models by blocking the production of immunostimulatory retroelement-derived DNA (Nature Medicine, 2019).

Other names

LINE-1 reverse transcriptaseL1-RTORF2pHERV reverse transcriptaseRetroelement reverse transcriptaseRNA-directed DNA polymerase

Inhibition of the enzymatic conversion of endogenous retroelement RNA (such as LINE-1 or HERV transcripts) into complementary DNA (cDNA), thereby preventing genomic integration and the accumulation of immunostimulatory cytoplasmic DNA that triggers the cGAS-STING pathway (Nature, 2019; Science, 2014).