The tumor suppressor protein p53 is a master regulator of gene expression that is involved in myriad cellular processes, from growth arrest to suicide to metabolism. It is also the most frequently mutated protein in human cancers. Modulation of which genes are controlled by p53 in a specific context underpins the cellular life-or-death balance, yet it is incompletely understood. In an August paper in the Proceedings of the National Academy of Sciences, Ludwig Oxford Director Xin Lu and her team reported a mechanism by which iASPP, an inhibitor of p53, influences p53’s selection of target genes. Using next generation sequencing, the researchers characterized the signature DNA sequences of genes that are jointly regulated by iASPP and p53. They also examined a crystal structure of the partnered proteins and found that iASPP disrupts a p53 domain that interacts with the signature sequences of iASPP co-regulated genes, providing an explanation for p53 target selection. iASPP’s interaction mode differs from previously characterized cellular p53 partners—though, intriguingly, overlaps with the interaction site of an oncoprotein from the cancer-causing pathogen HPV—and could open new opportunities for designing anticancer agents targeting p53.
This article appeared in the November 2019 issue of Ludwig Link. Click here to download a PDF (1 MB).