The WD40 domain-containing protein Wrap53 (WD40 encoding RNA Antisense to p53) is a scaffold protein implicated in Cajal Bodies maintenance, telomere elongation and DNA repair. WRAP53 loss of function has been related to carcinogenesis and premature aging. Double-strands breaks may result from ischemic stroke, thereby contributing to neuronal death and subsequent brain dysfunction. An adequate DNA damage response is essential to survive after cerebral ischemia and preserve the integrity of the transcribed genome in neurons. Although DNA repair pathways are active after ischemia, the molecular mechanisms underlying neuronal survival remain unknown. To investigate the role of Wrap53 in neuronal survival after ischemia, primary mouse cortical neurons were subjected to an experimental protocol of ischemia in vitro (oxygen and glucose deprivation) for 3 hours and were further incubated in regular medium (reoxygenation). We first observed that ischemia promoted DNA damage, as revealed by the accumulation of γH2AX and 53BP-1 in the neurons. Furthermore, we found a time-dependent increase in WRAP53 gene expression and protein abundance from 4 hours after the ischemic insult. In parallel, ischemia induced the traffic of Wrap53 to the nucleus, which has been associated to cell survival in tumor cells. Moreover, depletion of Wrap53 by siRNA increased neuronal susceptibility to ischemia-induced apoptosis. Our results demonstrate that ischemia-induced Wrap53 nuclear accumulation plays an essential role in neuronal survival.

Resumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016.

Funded by ISCIII (PI15/00473; RD12/0014/0007), FEDER, and Junta de Castilla y León (ISM).

Peer reviewed