p53 puzzle solved: How the most famous cancer-fighting gene works

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1. Please give a summary of your research.

My discovery tells a story of how p53, a most remarkable protein, protects us from developing cancer. p53 keeps our cells in order to make sure that they divide in a controllable manner. If a cell makes a mistake while copying its DNA during division, p53 stops cell division and recruits a DNA damage repair team. If the mistake in the genome cannot be corrected p53 can instruct the damaged cell to die. Critically, when p53 itself is faulty cancer will develop! For more than 30 years, medical researchers have been aware of the importance of p53 in preventing cancer, but how it performs its role has been a puzzle. Recent studies, including my own, overturned the dogma that p53 prevents development of cancer by instructing cells to die. My mission was to uncover the mysteries of this crucial tumour suppressor, and get into the heart of its function in preventing the cancerous transformation of cells. To address this question, I have performed innovative gene-editing screens in pre-clinical models of cancer. In the world’s first, I found that the coordination of several DNA repair is the most important process by which p53 prevents the development of cancer. In particular, I have demonstrated that when the expression of p53 regulated DNA repair genes is reduced, p53 cannot function properly, and unable to prevent tumour development. Amazingly, when I restored the natural levels of one of the members of the DNA repair team, Mlh1, in cells lacking p53, this was able to restore tumour suppression. The new understanding of the importance of DNA repair factors as the critical weapons for p53-mediated tumour suppression will stimulate new approaches for cancer therapy. I hope that in the future my discovery will transform the battle against cancer, particularly for tumours driven by defects in p53.

2. Please include any additional details you would like to share

Cancer is a disease that affects one of three of us at some point in our lives. The impact of my discovery is evident from the fact that p53 is mutated in half of all human cancers. Many pharma and biotech companies are working towards developing drugs to activate p53 in cancers with wild-type p53, or restoring wild-type p53 function in cancers driven by mutations in p53. However, there have been many difficulties in developing such strategies, and there is still extensive morbidity and mortality associated with cancers bearing p53 mutations. Given the obstacles to developing strategies for targeting wild-type or mutant, further understanding of basic p53 biology is required for successful clinical translation. My functional genetic screens in pre-clinical cancer models provided important insight for cancer researches around the world. They are bound to stimulate efforts to develop strategies to activate downstream p53 tumour suppressive functions for therapeutic gain in cancers rather than targeting p53 itself.


Publications related to this work:

1. Janic et al., DNA repair processes are critical mediators of p53-dependent tumor suppression. Nature Medicine, 2018.

2. Valente et al., Strasser* and Janic*. Combined loss of PUMA and p21 accelerates c-MYC-driven lymphoma development considerably less than loss of one allele of p53. Oncogene, 2016. *joint last authors

3. Valente et al., Janic* and Strasser*. p53 efficiently suppresses tumour development in the complete absence of its cell cycle inhibitory and pro-apoptotic effecters p21, Puma and Noxa. Cell Reports, 2013. *joint last authors



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