June 30, 2023

Zeroing in on how the ‘guardian of the genome’ works

The tumor suppressor protein p53 has been dubbed the ‘guardian of the genome’ because it protects the DNA from stress or long-term damage by regulating the expression of numerous genes involved DNA repair, cell division and cell death. Now, FMI researchers have homed in on some of the mechanisms that regulate the activation of p53 target genes.

By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors. The protein acts as a transcription factor that can be rapidly induced in response to various forms of cellular stress, resulting in immediate activation of genes involved in DNA repair, cell division and cell death.

Unlike many other transcription factors, p53 can bind closed chromatin — a tightly packed form of DNA and proteins that suppresses gene expression by making the genome inaccessible to transcription factors. But it’s unclear how p53 engages closed chromatin and opens it up to activate target genes.

Luke Isbel, a postdoctoral fellow in the Schübeler lab, and his colleagues investigated how p53 binds to DNA in mouse embryonic stem cells and human tissues. The researchers found that the protein binds tightly packed stretches of DNA in both the mouse and human genome, yet its ability to loosen chromatin and turn on genes is regulated by another protein called Trim24.

Trim24 localizes to p53 sites in closed chromatin, the researchers found. In the absence of Trim24, about half of 203 p53-regulated genes became strongly activated by p53.

The findings suggest that Trim24 typically limits p53 activity in closed chromatin, the researchers say. Because the levels of Trim24 are elevated in breast cancer and other types of tumors, the team speculates that the protein might limit the ability of p53 to function as a tumor suppressor in cancer cells.

Luke Isbel, Murat Iskar, Sevi Durdu, Joscha Weiss, Ralph S. Grand, Eric Hietter-Pfeiffer, Zuzanna Kozicka, Alicia K. Michael, Lukas Burger, Nicolas H. Thomä and Dirk Schübeler Readout of histone methylation by Trim24 locally restricts chromatin opening by p53 Nature Structural & Molecular Biology (2023) Advance online publication


About the first author
Luke Isbel was born near Sydney, Australia, and spent his childhood in northern Queensland, where he studied biomedical science at James Cook University. He then completed a PhD in mouse genetics at La Trobe University in Melbourne before joining the FMI in 2016. Luke is married and has an 18-month-old, and in his spare time he likes to brew beer and bake bread. During his time at the FMI, he received a Marie Sklodowska-Curie Actions Fellowship and an Australian National Health and Medical Research Council’s C.J. Martin Early Career Fellowship. Later this year, Luke will start his own lab at the South Australian Immunogenomics Cancer Institute (SAiGENCI), based at the University of Adelaide, for which he is welcoming inquiries from PhD students and postdocs keen to study gene regulation ‘down under’.

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