A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability.
Lin WangJingzheng LiHu ZhouWeidao ZhangJing GaoPing ZhengPublished in: Nature communications (2021)
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.
Keyphrases
- small molecule
- stem cells
- dna damage
- oxidative stress
- embryonic stem cells
- transcription factor
- induced apoptosis
- long non coding rna
- single molecule
- cell free
- type diabetes
- blood brain barrier
- dna methylation
- endothelial cells
- multiple sclerosis
- cell proliferation
- heat stress
- cell cycle arrest
- brain injury
- high glucose
- case control