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Bioinformatics to Help Understand Mechanisms of Cancerogenic Mutations

Quite a lot is known about how a cancer tumor develops, and a likely "culprit" of cancer has also been found – it is the accumulation of "mistakes" in genes that lead to the fact that mutant proteins are synthesized. Cells begin to randomly divide because of them instead of normal development. How exactly do these failures occur, and in general whether the genes or abnormally rapid accumulation of mutations in the DNA is the root? The answers to these questions are being searched by the scientists from different organizations, including the A.A.Harkevich Institute for Information Transmission Problems (RAS IPPI).

Vladimir Seplyarsky, junior researcher of the sector (№4) of molecular evolution of the IITP and the employee of the RNRMU and Lomonosov Moscow State University, told more about the research of the mechanism of accumulation of gene mutations under the 7th Moscow Conference on Computational Molecular Biology (MCCMB).

Highlight the suspects

"We do not calculate, due to which gene a normal somatic cell of the body turns into a cancerous one. I'm interested in the previous step: how mutations accumulate in a cancer cell", - the young scientist said.


According Seplyarsky, the bulk of the research of cancer pathologies is focused on the search for "broken" genes in a cancer cell now. And the processes, which are responsible for the preservation of the DNA and therefore are "the last bastion" in the fight against the accumulation of dangerous mutations, are not well understood.

Mutations occur in cells permanently, but most of them do not affect the function of the cells at all.

"Most of the mutations are of no importance. If the mutation is inherited, they do not affect the properties and the evolution of an organism. They make you neither man nor ape. But there are a huge number of quite specific mutational processes in cancers.

Abundance of mutations produced by these processes is that what changes the genes causing cancer. For example, skin cancer is caused by ultraviolet-caused mutations, lung cancer is caused by the cigarette smoke and cancer of the rectum – by violation of the system protects DNA from damage. Therefore, it is important to correlate the occurred mutations with mutational processes", – Seplyarsky said.

One of the main mutational processes in cancers (18% of reported cases) is caused by the antiviral protein – APOBEK, which normally provides a protective function. This protein mutates a viral DNA to save a cell from the virus.

"Virus DNA, unlike human one, passes through the stage when it is in a single stranded state (whereas it is a double-stranded helix in normal DNA). Then the protein sticks, DNA mutates, and the virus cannot function because a half of its positions is broken", – Seplyarsky said. But sometimes a protective protein "makes a mistake" and not a virus, but a human DNA gets hit.

When a human DNA is doubled, a full single-stranded state does not happen: DNA strands come apart and then polymerase "cars" go at once to synthesize new, complementary strands of DNA.

Yet new chains are synthesized in various ways, one of the strands (leading one) is synthesized continuously, and the second (trailing one) is synthesized by fragments – Okazaki fragments, and passes through the single stranded state. Despite the fact that single-stranded DNA on a lagging strand is "packed" in protective proteins, it is relatively vulnerable.


"These proteins primarily protect the molecule from damage, including do not let APOBEK attack its own DNA (while it is in a single stranded state). It is not clear what exactly happens in cancer cells, but APOBEK begins to heavily mutate human DNA –scientist continues. – It was unclear from where a single-stranded DNA, which is exposed to the "attacks" of the protein, appears. We suggested that this occurs near the sites where DNA is broken. But it seemed to me that a small number of breaks is not enough to explain the millions of made by APOBEK mutations observed in cancers. And

we hypothesized that the protein mutates lagging strand of DNA because it is well known: in case of any problems that arise during DNA duplication, trailing chain suffers the most.

To test the hypothesis, we have adapted computational method to cancer data to determine which of the strands is trailing and which is leading one. And finally we have shown that mutations caused by APOBEK lie on the trailing chain".

From fundamental to applied

Researches conducted by scientists can have a significant impact on our understanding of the nature of heredity and genetic glitches in organisms. As Seplyarsky noted, this basic research is nice and useful in itself. But in terms of practical application it also has great prospects.

Understanding of the mechanism of genetic malfunctions that lead to cancers is important to treat them, as well as timely diagnosis and determining the source of the disease.

"Why will it help us to cure cancer? Because we know now at which moment one of the most common mutational mechanisms of different cancers works: of breast cancer, bladder cancer, ovarian cancer, lung cancer. When it is known that the "attacker" protein sits on the lagging chain, we can think of special mechanisms that will uptake this complex and kill cancer cells only. Because nothing like this happens in normal cells. If this happens, they immediately accumulate mutations and become cancer cells".

Of course, the search for such drugs – is the matter of the future, but due to conducted research, biologists and physicians now know where to look, Seplyarsky is sure.

"In fact, this work has a continuation – young scientist shared in conclusion– Further I'm still trying to find some damage, a gene that allows APOBEKU reach a single-stranded DNA. I have some hypotheses, and if they are correct, it will give a pretty strong treatment "in a single step".

So there is a some hope cancer will be at last defeated using mechanisms that are more powerful that existing ones, like chemical therapy and even immune therapy.


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