Sunday , January 29 2023

Mutagenic protein draws attention to the DNA guardian to promote cancer development


Scientists from Melbourne have discovered how tumor development is determined by the mutation in the key prevention of genetic cancer, p53.

The study found that in the early stages of cancer, the p53 mutation "solves" the normal p53 protein and prohibits it from exercising its protective role. As a result, p53 can no longer activate natural anti-cancer protection, such as the body's DNA repair process, increasing the risk of cancer.

The research was led by Dr. Brandon Obri, Professor Andreas Strasser and Dr. Gemma Kelly with Professor of Bioinformatics Gordon Smith and Dr. Yunshun Chen. Opinions are published in this month's edition Genes and development.

in short

Researchers have discovered that p53 mutations found in half of all human cancers lead to cancerous development.

The mutant p53 protein "solves" the normal protein and prevents it from performing its protective layer, while allowing the activation of tumors that affect the growth of the genes.

The team now checks that the mutated p53 protein works in tumors of the same types and has a significant effect on cancer therapy.

Fighting DNS Guardian

P53 is known as the "genome guard" due to the fact that it protects cells from cancer.

"P53 plays an important role in many pathways that prevent cancer, such as DNA repair or cell death if they have irreversible DNA damage," said Dr. Kelly.

"P53 genetic defects are found in half of all human cancers, but just as these changes interfere with the p53 function, it has long been a mystery."

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

"During the early development of cancer, one gene copy may suddenly and continuously change by mutation, while the other gene copy remains normal, creating a cell that forms a mixture of normal and mutant variants of the p53 protein.

"We found that the mutational p53 protein can bind to and" prevent normal protein p53 "by preventing it from performing protective functions such as DNA reconstruction. Thus, the cell is more likely to cure additional genetic changes that accelerate tumor development."

The team hoped that mutant proteins would block all normal p53 activity, so it was surprising that only certain p53 dependent pathways were affected.

"Mutagenic proteins are tricky: while p53 bans the activation of pathways that protect against cancer, they still allow p53 to activate pathways that promote tumor growth." P53 cancer is obviously more complicated than we expected, "said Dr. Kelly.

The secret is resolved

Professor Strasser said that the findings report a long debate on the p53 mutation.

"Scientists have discussed how p53 mutations contribute to the development of cancer for decades.

"One camp claims that the mutant p53 works by" solving "the normal protein and blocking its natural defense role. The other camp claims that the mutant p53 goes hand in hand and carries out new roles that promote tumor development."

"Our work clearly shows that during the development of cancer, the usual p53" fight "is the most important. It selectively excludes certain but not all of the usual p53 functions," said Professor Strasser.

Clinical effects

The team will now investigate whether the same applies to detected tumors and this has a significant impact on drug treatment.

"Established tumors often lost their normal copy of the p53 gene and only produce mutant p53 proteins," said Dr. Kelly.

"If the mutation of p53 works by combating normal p53, then it no longer has any relevance in detecting tumors in the absence of normal p53, which would mean that the drugs that block the p53 mutation would not have a clinical advantage," she said.

"Contrary to the fact that p53 is a novel cancer-promoting activity associated with the detection of tumors, medicines specifically blocking the mutation of p53 may be useful for treating thousands of patients."

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