APOBEC Double Agent
Biologists from IPPR RAS have learned how mutations leading to cancer arise
Maria Efimova
Bioinformatics from the A.A. Harkevich Institute of Information Transmission Problems of the Russian Academy of Sciences (IPPR RAS) and the University of Geneva were able to prove that most of the mutations leading to the development of 18 percent of cancerous tumors occur during DNA replication. The results of the study are described in an article published on February 1 in the journal Genome Research (Seplyarskiy et al., APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication).
Mutations in the DNA of human somatic cells lead to the transformation of a healthy cell into a cancerous one, the subsequent development of the disease, and the acquisition of resistance to anti-cancer therapy. APOBEC is an antiviral defense protein that causes changes in the DNA or RNA of viruses, but in a cancer cell it "attacks its own" and "attacks" human DNA. Thus, in 18 percent of cancerous tumors, APOBEC strongly mutates the host DNA in tumor cells. However, APOBEC is not capable of altering normal double-stranded human DNA, and how it causes mutations in it remained unknown.
A group of bioinformatics scientists from the Molecular Evolution Sector of the IPPR RAS managed to shed light on this issue. Scientists have shown that most of the mutations caused by APOBEC occur during DNA replication, in those short periods of time until the DNA strands are paired with each other. The DNA chain replicating as lagging remains single longer; accordingly, most of the mutations caused by APOBEC occur on it.
"The mutation process for various cancers is very specific: for example, smokers' cancer occurs due to mutations caused by substances in cigarette smoke, and basal carcinoma or melanoma - due to exposure to sunlight. However, there are processes that lead to mutations for many types of cancer at once, one of the main ones among them is mutations caused by the activity of the APOBEC protein attacking single–stranded DNA," explained the author of the project and the first author of the article Vladimir Seplyarsky.
According to the young scientist, it is likely that the results obtained in their subsequent development will lead to a deeper understanding of what is happening in cancer and somatic cells and, as a result, to the creation of anti-cancer therapy.
About the illustration:
"The Tale of the Three Piglets" in the context of human mutagenesis. Piglet brothers are cytosines in the context of TpCpA (a specific context for mutations left by APOBEC) during DNA replication. The youngest piglet (closest to the viewer) is cytosine, has built a straw house on a lagging DNA chain and is subject to attacks by the Aries wolf. The average piglet is methylated cytosine, built a wooden house and is better protected (DNA methylation somewhat protects against APOBEC). The safest stone house – cytosine in double–stranded DNA, which is not replicated yet - belongs to the older brother.
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03.02.2015