iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
Chen S., Wu J., Zhong S., Li Y., Zhang P., Ma J., Ren J., Tan Y., Wang Y., Au KF., Siebold C., Bond GL., Chen Z., Lu M., Jones EY., Lu X.
Significance TP53 , encoding p53, is the most frequently mutated gene in human cancers. p53 is a transcription factor that suppresses tumors by regulating myriad genes critical for diverse cellular outcomes including growth arrest and death. This study addresses the mechanism by which iASPP, a p53 partner, influences p53 target gene selection. Using next-generation sequencing, we found genes coregulated by iASPP and p53, and characterized their DNA sequence signatures. Our crystal structure of iASPP and p53 reveals that iASPP displaces a loop of p53 that recognizes DNA signatures. iASPP inhibits p53 through a protein surface distinct from other characterized p53 cellular partners but overlapping that targeted by the viral oncoprotein human papillomavirus E6. These findings open prospects for designing p53-targeting anticancer agents.