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Mutant proteins handle guardian DNA to promote cancer development



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Melbourne scientists have discovered how tumor development is driven by mutations in the most important genes to prevent cancer, p53.

This study revealed that in the early stages of cancer, p53 mutants' handle & # 39; normal p53 protein and blocks it from carrying out its protective role. As a result, p53 can no longer activate natural defenses against cancer – such as the body's DNA repair process – increasing the risk of developing cancer.

The study was led by Dr. Brandon Aubrey, Professor Andreas Strasser and Dr. Gemma Kelly along with bioinformatics, Professor Gordon Smyth and Dr. Yunshun Chen. This finding is published in this month's edition Genes and Development.

At a glance

Researchers have discovered how mutations in p53 – found in half of all human cancers – encourage the development of cancer.

Mutant p53 protein handle & # 39; normal protein and prevent it from carrying out its protective role, while allowing it to activate genes that encourage tumor growth.

The team is now examining whether mutant p53 protein acts the same way in existing tumors, with important implications for cancer therapy.

Handle DNA guardians

p53 is known as the 'guardian of the genome & # 39; because of its role in protecting cells from cancer.

"P53 plays an important role in many pathways that prevent cancer, such as repairing DNA or killing cells if they have irreparable DNA damage," Dr. Kelly said.

"Genetic abnormalities in p53 are found in half of all human cancers, but how this change disrupts the function of p53 has long been a mystery."

Dr. Kelly said that cells usually have two copies of the p53 gene in each cell.

"In the early stages of cancer development, one copy of a gene can undergo sudden and permanent changes through mutations, while copies of other genes remain normal. This produces cells that make a mixture of normal and mutant versions of the p53 protein.

"We found that mutant p53 protein can bind and" normal "p53 protein, blocking it from carrying out protective roles such as DNA repair. This makes cells more likely to experience further genetic changes that accelerate tumor development."

The research team hopes that mutant proteins will block all normal p53 activity, so were surprised to find that only certain p53-dependent pathways were affected.

"The mutant protein is cunning: while they stop p53 from activating pathways that protect against cancer, they still allow p53 to activate pathways that encourage tumor growth. The role of p53 in cancer is clearly more complicated than we thought," Dr. Kelly said.

A mystery is overcome

Professor Strasser said these findings inform the longstanding debate about mutant p53.

"Scientists have debated how the mutants of p53 contribute to the development of cancer for decades.

"One camp argues that mutant p53 acts by overcoming normal proteins and blocking its natural protective role. Other camps argue that mutant p53 becomes naughty and performs new roles that encourage tumor development."

"Our work clearly shows that during the development of cancer," normal handling "was the most significant. This selectively deactivates certain functions but not all normal p53, said Professor Strasser.

Clinical implications

The team is now investigating whether the same applies to existing tumors, with important implications for drug treatment.

"Established tumors often lose normal copies of their p53 gene and only produce mutant p53 proteins," said Dr. Kelly.

"If mutant p53 acts by handling normal p53, then it may no longer play a role in tumors that have already formed where no normal p53 is produced. This means that drugs that block mutant p53 will not have clinical benefits," he said.

"Conversely, if mutant p53 has a new activity, promoting cancer itself in existing tumors, then drugs that specifically block mutant p53 can be useful for treating thousands of patients."

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