CTCF regulates the human p53 gene through direct interaction with its natural antisense transcript, Wrap53.
The multifunctional CCCTC-binding factor (CTCF) protein exhibits a broad range of functions, including that of insulator and higher-order chromatin organizer. We found that CTCF comprises a previously unrecognized region that is necessary and sufficient to bind RNA (RNA-binding region [RBR]) and is distinct from its DNA-binding domain. Depletion of cellular CTCF led to a decrease in not only levels of p53 mRNA, as expected, but also those of Wrap53 RNA, an antisense transcript originated from the p53 locus. PAR-CLIP-seq (photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation [PAR-CLIP] combined with deep sequencing) analyses indicate that CTCF binds a multitude of transcripts genome-wide as well as to Wrap53 RNA. Apart from its established role at the p53 promoter, CTCF regulates p53 expression through its physical interaction with Wrap53 RNA. Cells harboring a CTCF mutant in its RBR exhibit a defective p53 response to DNA damage. Moreover, the RBR facilitates CTCF multimerization in an RNA-dependent manner, which may bear directly on its role in establishing higher-order chromatin structures in vivo.
Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, México City 04510, México;
Ricardo
R
Saldaña-Meyer
Edgar
E
González-Buendía
Georgina
G
Guerrero
Varun
V
Narendra
Roberto
R
Bonasio
Félix
F
Recillas-Targa
Danny
D
Reinberg
D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D005786:Gene Expression Regulation; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D018832:Molecular Chaperones; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D012313:RNA / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D019098:Telomerase / Q000378:metabolism*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D018832:Molecular Chaperones; D012097:Repressor Proteins; D012313:RNA; D019098:Telomerase; C535133:WRAP53 protein, human
CTCF; RNA binding; Wrap53; multimerization; p53