How DNA mutations are introduced in tumor
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Research published in the journal Cell Reports, shows how the expression of a protein causes mutations to accumulate in actively replicating DNA. The work is complemented by studies from other researchers published in the Proceedings of the National Academy of Sciences and Cell, which indicate that similar phenomena occur in E. coli cells and sequenced human tumors.
Researchers introduced the protein, an enzyme with the shorthand name of APOBEC, into a laboratory strain of the baker's yeast Saccharomyces cerevisiae. They documented how it mutated genetic sequences in a small region of just three nucleotides, the subunits of DNA.
The protein normally kills viruses by making changes to their genetic sequence, inactivating them. But the protein can also change the genetic sequence of a normal cell, altering the body's blueprint and making mutations that cause cancers.
"What we found is the way that the proteins are making these mutations in tumors is they actually take advantage of the fact that tumors are dividing a lot, so they're able to damage DNA that's being actively replicated," said the lead author of the paper.
As DNA replicates, it has moments in which single strands of its double helix are exposed. The APOBEC protein takes advantage of this vulnerability to cause damage by deaminating the lagging strand of the DNA. Prior studies have found that one in five human tumors have evidence of these enzyme-induced mutations.
In addition to causing tumors, the protein can continue to mutate tumor DNA, increasing a cancer's genetic diversity and giving it a wider tool kit with which to resist treatment.
A greater knowledge of how APOBEC works could lead to treatments that decrease its activity, said Roberts. Or a treatment could go in the other direction, creating so many mutations in a tumor that it self-destructs.