“Speckle” Structures Believed to Partner With p53 in Cancer Activity

A recent study that provides new insights into basic cell biology could lead to an improved understanding of cancers and possible treatments.

The study, published in Molecular Cell, identifies the tumor-suppressing protein p53 as a working partner of “speckles,” nuclear structures that contain proteins and RNA involved in gene expression.

Speckles, once thought to serve as more of a storage function, are now believed to work with p53 to directly enhance the activity of certain genes, with p53 affecting a subset of its target genes via these nuclear speckles. p53 brings together speckles and DNA-containing target genes; when they get close, the level of transcription of the genes jumps significantly.

The researchers also found that the p53 target genes whose activity is boosted via speckles have a set of functions that are broadly distinct from those of other p53 target genes.

“This study shows that nuclear speckles work as major regulators of gene expression, and suggests that they have a role in some cancers,” study senior author Shelley Berger, PhD, the Daniel S. Och University Professor in the Department of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, said in a statement.

“Speckle-associated p53 target genes, compared to other p53 target genes, are more likely to be involved in tumor-suppressing functions such as stopping cell growth and triggering cell suicide,” said first author Katherine Alexander, PhD, a postdoctoral researcher in the Berger Laboratory.

p53 is known to be disrupted in about half of all cancers; it can also be mutated so that it not only loses its tumor-suppressor function, but may also promote metastasis.

Scientists now want to see if nuclear speckles are involved in mediating p53’s cancer-driving effect.

“If that proves to be the case,” Berger said, “then in principle we could develop treatments to interfere with this association between p53 and speckles—an association that might turn out to be a real Achilles heel for cancer.

Reference

Alexander KA, Coté A, Nguyen SC, et al. p53 mediates target gene association with nuclear speckles for amplified RNA expression. Molecular Cell. Published online April 05, 2021. doi: 10.1016/j.molcel.2021.03.006