A new study found that a protein that usually fights viral infections may not be as beneficial as previously believed. In fact, it may even trigger cancer.
Researchers discovered that a protein called APOBEC induces mutations by taking advantage of the weak part of the DNA replication process.
APOBEC, while useful and protective against viral infections, may also be hazardous. The protein can only modify single-stranded DNA such as those found in viruses. Once a double-stranded DNA comes in contact with it, APOBEC does not alter or cause any effects. Researchers, however, found that APOBEC can be found in numerous tumors in the entire genome.
The goal of the DNA replication process is to create two identical copies of the original DNA. The process requires tedious, precise and well-timed mechanisms. The two strands from the original DNA, together with the new ones, will create what is known as the genetic fork.
The direction of the genetic fork will dictate the different processes that influence how the strands replicate.
Technically when the two strands separate, it becomes single-stranded. However, in cases when one of the two strands are created immediately, the other one cannot be constructed as swiftly. With this, the "leading strand" does not exist as a single-stranded DNA. The other one, the "lagging strand," continues to be single-stranded for a time.
Because researchers very well know that APOBEC only affects single-stranded DNA, they need to determine the direction of the replication fork to see which DNA regions stay single-stranded for prolonged periods.
They discovered twice as many mutations in the lagging strand than in the leading strand. This means that APOBEC takes advantage of the time when the lagging strand is still single-stranded and at the same time, weaker.
The most well-protected genes replicate early, leaving the genomes that replicate late prone to mutation. In fact, mutations in genome areas that replicate during the latter phase are three times higher in number.
With APOBEC cancer, the mutations develop at the beginning stages of replication and thus affect the most vital genes.
"We were very surprised to observe that, in APOBEC cancers, the mutation rate is equally distributed in all regions," says first author Vladimir Seplyarskiy from the Russian Academy of Sciences.
APOBEC seems to act like a marker or a gate-keeper that lets opportunistic mutagens attack at the early stages. With this, the researchers say genome regions that replicate early must not stay single-stranded long enough for APOBEC to attack. This may also mean that something is faulty even before APOBEC enters the scene, says Seplyarskiy.
Further research is needed to determine the DNA replication differences between cancerous and healthy cells.
The study was published in the journal Genome Research.
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