114
Enhancing Translation of LINE-1 Encoded ORF2p for Cancer Therapeutics
Johns Hopkins University
Small molecule
Oncology
Hit To Lead or Lead Optimization
• ORF2p translation could activate by the bi-cistronic LINE-1 RNA.
• A case of colon cancer with an aggressive tumor subclone that shut down LINE-1 expression concurrent with its accelerated growth.
• LINE-1 triggers a tumor protein p53 (TP53)-mediated G1 arrest and an interferon response in nontransformed cells.
• In TP53-deficient cells, inventor conducted a knockout screen to identify genes that affect the fitnesss of LINE-1+ cells. LINE-1+ cells rely on replication-coupled DNA-repair pathways, replication-stress signaling responses and replication-fork restart factors for growth.
• LINE-1 expression activates the Fanconi anemia pathway, induces markers of replication stress and sensitizes cells to mitomycin C (MMC). Inventor proposes a model for LINE-1 toxicity wherein LINE-1 retrotransposition conflicts with DNA replication.
WO2021134040A2
LINE-1 ORF2p expression is nearly imperceptible in human cancers. Mob DNA. (2019)
Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication. Nat Struct Mol Biol. (2020)