A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability

RPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the guardian of RPA availability in stem cells. Discn is induced upon genotoxic stress and binds to neucleolin (NCL) in the nucleolus. This prevents NCL from translocation into nucleoplasm and avoids undesirable NCL-mediated RPA sequestration. Thus, Discn-NCL-RPA pathway preserves a sufficient RPA pool for DNA replication stress response and repair. Discn loss causes massive genome instability in mouse embryonic stem cells and neural stem/progenigor cells. Mice depleted of Discn display newborn death and brain dysfunctions due to DNA damage accumulation and associated inflammatory reactions. Our findings uncover a key regulator of DNA metabolism and provide new clue to understand the chemoresistance in cancer treatment. Various lncRNAs functions have been associated to replication stress and DNA double strand breaks in ESC. Here the authors reveal the lncRNA Discn-NCL-RPA axis pathway, which can regulate the availability of RPA pool for DNA replication stress response and repair.

Automated summary

The novel lncRNA Discn acts as a guardian of RPA availability in stem cells by regulating NCL activity to maintain a sufficient RPA pool. Loss of Discn leads to genome instability, newborn death, and brain dysfunctions in mice, highlighting its critical role in DNA metabolism and chemoresistance in cancer treatment.