Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage.
Antisense transcription is a widespread phenomenon in the mammalian genome. It is thought to play a role in regulation of gene expression, but its exact functional significance is largely unknown. We have identified a natural antisense transcript of p53, designated Wrap53, that regulates endogenous p53 mRNA levels and further induction of p53 protein by targeting the 5' untranslated region of p53 mRNA. siRNA knockdown of Wrap53 results in significant decrease in p53 mRNA and suppression of p53 induction upon DNA damage. Conversely, overexpression of Wrap53 increases p53 mRNA and protein levels. Blocking of potential Wrap53/p53 RNA hybrids reduces p53 levels nearly as efficiently as Wrap53 knockdown, strongly suggesting that Wrap53 regulates p53 via Wrap53/p53 RNA interaction. Furthermore, induction of Wrap53 sensitizes cells for p53-dependent apoptosis. This discovery not only reveals a regulatory pathway for controlling p53, but also proposes a general mechanism for antisense-mediated gene regulation in human cells.
Mahmoudi
Salah
S
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
Henriksson
Sofia
S
Corcoran
Martin
M
Méndez-Vidal
Cristina
C
Wiman
Klas G
KG
Farnebo
Marianne
M
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D034622:RNA Interference; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D018832:Molecular Chaperones; D016372:RNA, Antisense; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D019098:Telomerase; C535133:WRAP53 protein, human