Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

Abstract

The transcription factor (TF) p53 is the best-known tumor suppressor, but its ancient sibling p63 (ΔNp63) is a master regulator of epidermis development and a key oncogenic driver in squamous cell carcinomas (SCC). Despite multiple gene expression studies becoming available in recent years, the limited overlap of reported p63-dependent genes has made it difficult to decipher the p63 gene regulatory network (GRN). In particular, analyses of p63 response elements differed substantially among the studies. To address this intricate data situation, we provide an integrated resource that enables assessing the p63-dependent regulation of any human gene of interest. Here, we use a novel iterative de novo motif search approach in conjunction with extensive publicly available ChIP-seq data to achieve a precise global distinction between p53 and p63 binding sites, recognition motifs, and potential cofactors. We integrate all these data with enhancer-gene associations to predict p63 target genes and identify those that are commonly de-regulated in SCC and, thus, may represent candidates for therapeutic interventions.

Mice Are Not Humans: The Case of p53

“…Because of their highly conserved DNA binding domain (DBD), p53 homologs from multiple species can specifically trans-activate a common cisregulatory element, the p53 response element (p53RE). The p53 family DBD recognizes two decameric half sites with consensus sequences that differ slightly between the family members: p53 prefers RRRCWWGYYY, while p63 binds RRRCNNGYYY (R=A/G, W= A/T, Y= C/T, N=A/T/G/C) [9]. Notably, most p53REs also function as p63RE and many p63REs serve as p53REs.…”

Tumor suppressor p53: from engaging DNA to target gene regulation

“…Like TAp63, full-length p73 (TAp73) is a haplo-insufficient tumor suppressor and it functions as a key regulator of neuronal development, multi-ciliated cell differentiation, and metabolism ( 171 , 174 ). The p53 family shares highly-related DNA binding domains with similar, but not identical, RE sequence preferences ( 88 , 175 ). Consequently, the p53 TF family shares many binding sites; however, all three family members also display substantial subsets of unique target genes ( 12 , 175 , 176 ).…”

“…The p53 family shares highly-related DNA binding domains with similar, but not identical, RE sequence preferences ( 88 , 175 ). Consequently, the p53 TF family shares many binding sites; however, all three family members also display substantial subsets of unique target genes ( 12 , 175 , 176 ). Understanding the interplay between p53, p63, and p73 is complicated by the differential function of several N- and C-terminal isoforms of all three family members that exhibit overlapping targets with often antagonistic function within and between the family members ( 177 , 178 ).…”