Abstract
ΔNp63α-dependent SRCAP recruitment and H2A.Z deposition suppress target gene expression.
Major finding: ΔNp63α-dependent SRCAP recruitment and H2A.Z deposition suppress target gene expression.
Concept: ΔNp63α does not prevent p53 binding at shared binding sites and regulates a unique set of genes.
Impact: H2A.Z-mediated transcriptional repression may underlie the oncogenicity of ΔNp63α.
ΔNp63α is a member of the p53 family of transcription factors that is generated by alternative promoter usage at the TP63 locus. ΔNp63α promotes stem cell proliferation in stratified epithelia and is a potent oncogene in squamous cell carcinomas (SCC) in multiple tissues. Because ΔNp63α recognizes similar DNA sequence motifs as p53 but lacks an N-terminal transactivation domain, it has been presumed that ΔNp63α represses p53 target genes in a dominant negative manner by competing for p53 binding. To determine whether ΔNp63α is a dominant negative inhibitor of p53, Gallant-Behm and colleagues analyzed the functional relationship between these proteins in SCC cells. ΔNp63α and p53 knockdown affected the expression of largely nonoverlapping sets of genes, and p53 binding still occurred at genes that were repressed by ΔNp63α. Moreover, ΔNp63α loss arrested the proliferation of SCC cells regardless of p53 status. Together, these data establish that ΔNp63α does not compete with p53 for binding to target loci and suggest that the role of ΔNp63α in SCC is p53 independent. To gain mechanistic insight into how ΔNp63α regulates gene expression, the authors identified ΔNp63α-interacting proteins by tandem affinity purification followed by mass spectrometry. ΔNp63α bound several subunits of the SRCAP complex, a chromatin remodeling complex that mediates exchange of histone H2A with the variant histone H2A.Z. ΔNp63α was required for SRCAP complex recruitment and H2A.Z deposition at target genes, and knockdown of SRCAP subunits or H2A.Z led to derepression of ΔNp63α target genes. Interestingly, several ΔNp63α target genes repressed by deposition of H2A.Z inhibit cancer cell proliferation, suggesting that ΔNp63α overexpression may promote the progression of SCC by establishing repressive chromatin states at antiproliferative genes.
RSS Feeds