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Posted: Mar 30, 2015
How DNA alarm-system works
(Nanowerk News) The DNA molecule is chemically unstable giving rise to DNA lesions of different nature. That is why DNA damage detection, signaling and repair, collectively known as the DNA damage response, are needed. The DNA damage response is immensely important, for example, for ensuring the highest possible quality of the DNA before replication - duplication of the DNA prior to cell division. If the damaged DNA is replicated, the risk of cancer and other diseases increases significantly due to mutations. All in all this may lead to the death of a cell itself.
DNA repair consists of enzymes which find the damaged DNA and repair it before the replication. These enzymes work differently. Some of them recognize the damaged bases and give signals to the other enzymes, which repair the DNA.
DNA repair is shown. (Image: Courtesy of Tom Ellenberger, Washington University School of Medicine in St. Louis)
Ataxia-telangiectasia mutated (ATM) is a kinase that transmits the signal from damaged DNA to cellular repair systems. Scientists used to think that ATM exclusively recognizes DNA double-strand breaks (DSBs). These breaks are extremely dangerous because they may lead to the loss of genetic information.
Svetlana V. Khoronenkova who is a Postdoctoral Researcher at Lomonosov Moscow State University and at the University of Oxford was among the scientists who managed to discover a novel role for ATM. She designed the project, controlled its experimental part and prepared the results for the publication. The article written by Svetlana V. Khoronenkova and her colleague Grigory L. Dianov was published in PNAS ("ATM prevents DSB formation by coordinating SSB repair and cell cycle progression").
"Endogenous double-strand breaks are rarely formed in the DNA. The concept of the cellular function lies in the prevention of DNA double-strand break's formation", -- Svetlana V. Khoronenkova said, -- "We now understand that ATM recognizes and is activated in response to DNA single-strand breaks (SSBs)".
Svetlana V. Khoronenkova mentioned that about 15 to 20 thousand endogenous DNA single-strand breaks form per day. On the other hand, only 10-20 DNA double-strand breaks are formed during this period. This highlights the importance of signaling the presence of unrepaired DNA single-strand breaks to repair systems.
In response to DNA single-strand breaks ATM self- activates and transmits the signal about the damage.
This leads to a delay in the DNA replication, giving a cell more time to repair.
If timely repair does not occur, replication over the SSB-containing DNA results in the formation of deleterious DSBs, thus increasing the risk of cancer and other diseases.
In particular, mutations in the ATM gene are associated with Ataxia telangiectasia (A-T), a rare inherited disease with symptoms in early childhood and a short life span. Overall, there is about one documented case in 40,000-100,000 births worldwide, and about 1% of the world's population carry mutations in ATM. In addition to immunodeficiency and neurodegeneration, A-T is characterised 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 with the development of new therapies, and in an attempt to improve the lives of those who suffer from A-T and diseases with the similar phenotype", -- Svetlana V. Khoronenkova summarized.