A protein that usually fights viral infections may also cause cancer by taking advantage of a weakness in DNA replication process to induce mutations in our genome, a new study has found.
Cancer is caused by the growth of an abnormal cell which harbours DNA mutations, ‘copy errors’ occurring during the DNA replication process.
If these errors do take place quite regularly without having any damaging effect on the organism, some of them affect a specific part of the genome and cause the proliferation of the mutant cell, which then invades the organism, according to researchers from the University of Geneva (UNIGE) and Russian Academy of Sciences.
APOBEC, which usually functions as protecting agent against viral infection, is a useful, yet dangerous, intrinsic cellular protein. It has only the power of modifying single-stranded DNA - viral DNA being frequently single-stranded.
Our double-stranded human DNA should therefore not be altered. But researchers have observed that mutations induced by APOBEC can be found in many tumorous cells, throughout the genome.
Scientists have already brought the evidence that about 20 per cent of APOBEC mutations originate from an abnormality in the DNA, called ‘double-stranded breaks’ which leaves, for a period of time, a part of DNA in a single-stranded state. It is this particular moment that APOBEC targets to cause multiple mutations.
Researchers have now understood the mechanism governing the remaining 80 per cent of APOBEC-related mutations.
During the cell division process, the DNA must be replicated according a precise process and timing to produce two identical copies from the original DNA. The replication begins at a specific location.
The separation of the two original strands and the synthesis of the new ones then result in a replication fork - the new strands are rebuilt as the fork moves along the chromosome, researchers said.
During DNA replication, the two strands are replicated by different mechanisms which depend on the direction of the replication fork. If one of the two strands is constructed right away, the second one cannot be reconstructed as quickly.
As a result, one strand, the ‘leading strand’, never exists as single-stranded DNA, whereas the other one, the ‘lagging strand’, remains single-stranded for some time.
“We were able to identify the direction of the replication fork for about 20 per cent of the genome, and found twice as many mutations on the lagging strand, compared with the leading strand,” said Sergey Nikolaev from UNIGE.
With this discovery, scientists brought evidence that APOBEC takes advantage of the moment when the lagging strand remains single, therefore weaker.
The findings were published in the journal Genome Research.