October 4, 2022

How does the alarm system of the DNA work?

The DNA molecule is chemically unstable by providing DNA lessons of different natures.

That is why DNA damage, signalization and repair, commonly known as a reaction to DNA damage, is needed.

Reaction to DNA damage is extremely important, for example, to ensure the highest possible quality of DNA before replication – doubling the DNA before cell division. If the damaged DNA is replicated, the risk of cancer and other diseases increases significantly due to mutations. In general, this may lead to the death of the cell itself.

DNA repair consists of enzymes that find damaged DNA and repair it before being replicated. These enzymes work differently. Some of them know the damaged bases and give signals of other enzymes that repair DNA.

Ataxy-mutated telangiectasia (ATM) is a kinase that transmits the signal from damaged DNA to the cellular repair systems. Scientists felt that ATM alone recognizes double stranded DNA (DSB). These fractures are extremely dangerous because they can lead to the loss of genetic information.

Svetlana V. Khoronenkova, who is an academic scholar at Moscow State University’s Lomonosov University and Oxford University, was among the scientists who came to discover a new role for ATMs. She designed the project, controlled its experimental part, and prepared the results for publication. The article written by Svetlana V. Khoronenkova and her colleague Grigory L. Dianov was published in PNAS.

“Two-stranded endogenous breakdowns are rarely formed in DNA. The concept of cellular function lies in preventing the formation of DNA bipolar disruption,” said Svetlana V. Khoronenkova. “We now understand that ATM is recognized and activated in the SSB reaction with SSB.”

Svetlana V. Khoronenkova mentioned that about 15-20,000 endogenous stranded DNAs are formed per day. Conversely, only 10-20 DNA with two-stranded fractures are formed during this period. This highlights the importance of signaling the presence of unrefined DNA with one-tier fracture to repair the systems.

In a single stranded DNA reaction, the ATM self-activates and transmits the signal with respect to the damage.

This leads to a delay in DNA replication, giving the cell more time to repair.

If timely repair can not occur, replication on SSBs containing SSB results in the formation of harmful DSBs, increasing the risk of cancer and other diseases.

In particular, mutations in the ATM gene relate to ataxia-telangiectasis (A-T), a rare disease inherited with early childhood symptoms and a short lifespan. In general, there is about one documented case in 40,000-100,000 births around the world, and around 1% of the world’s population carry ATM mutations. In addition to immunity and neurodegeneration, A-T is characterized by extreme sensitivity and predisposition to cancer.

“Now we want to understand how ATM is activated in response to SSBs. This future work will ultimately help develop new therapies, and in an effort to improve the lives of those who suffer from AT and illnesses with similar phenotype “, – summed up Svetlana V. Khoronenkova

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