Nuclear WRAP53 promotes neuronal survival and functional recovery after stroke.

Abstract

Failure of neurons to efficiently repair DNA double-strand breaks (DSBs) contributes to cerebral damage after stroke. However, the molecular machinery that regulates DNA repair in this neurological disorder is unknown. Here, we found that DSBs in oxygen/glucose-deprived (OGD) neurons spatiotemporally correlated with the up-regulation of WRAP53 (WD40-encoding p53-antisense RNA), which translocated to the nucleus to activate the DSB repair response. Mechanistically, OGD triggered a burst in reactive oxygen species that induced both DSBs and translocation of WRAP53 to the nucleus to promote DNA repair, a pathway that was confirmed in an in vivo mouse model of stroke. Noticeably, nuclear translocation of WRAP53 occurred faster in OGD neurons expressing the Wrap53 human nonsynonymous single-nucleotide polymorphism (SNP) rs2287499 (c.202C>G). Patients carrying this SNP showed less infarct volume and better functional outcome after stroke. These results indicate that WRAP53 fosters DNA repair and neuronal survival to promote functional recovery after stroke.

• Authors: Irene Sánchez-Morán, Cristina Rodríguez, Rebeca Lapresa, Jesús Agulla, Tomás Sobrino, José Castillo, Juan P Bolaños, Angeles Almeida
• Journal: Science advances (Sci Adv) Vol. 6 Issue 41 (10 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 33028529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Chemical References

• Molecular Chaperones
• Transcription Factors
• Telomerase
• WRAP53 protein, human
• Glucose

Topics

• Animals
• Cell Nucleus (metabolism)
• Cell Survival (genetics)
• DNA Repair
• Glucose (metabolism)
• Humans
• Mice
• Molecular Chaperones (metabolism)
• Neurons (metabolism)
• Stroke (genetics, metabolism)
• Telomerase (metabolism)
• Transcription Factors (metabolism)