DNA’s 'Gap in the Armor' Allowing Cancer to Develop Pinpointed

A key group of enzymes could be the “gap in the armor” of all DNA, allowing cancer-causing mutations, according to a new study.

APOBEC3G, which is known to trigger benign mutations, also causes malignant mutations during the DNA replication process, according to the new findings, in the Proceedings of the National Academy of Sciences.

“Many tumors accumulate mutations during their growth, which leads to the subsequent characteristics that permit metastasis,” said Patricia Foster, professor at Indiana University, and senior author. “Based upon the results revealed in bacteria in our study, we believe that the APOBEC family of enzymes create some of these mutations specifically during the rapid growth of these tumors.”

The investigators created and observed the mutations in the bacteria Escherichia coli, which presented the advantage of watching thousands of generations in a relatively short time.

The key process is the movement of DNA polymerase along one of the two DNA single strands, known as the lagging strand template, during the replication process. The lagging strand becomes susceptible to errors. APOBEC can enter into this process, causing cytosine deamination, essentially replacing the intended cytosine on the strand with the thymine nucleobase, causing the mutations.

The scientists turned off the ability to regulate the cytosine deamination in the E. coli replication – and then observed an uptick in the harmful mutations confirming the culprit, they said.

“These results strongly suggest that these mutations occur as APOBEC3G attacks cytosines during DNA replication, while they’re most exposed on the lagging strand template,” said Foster. “This basic mechanism appears to be the same in bacteria and in human tumor cells.”

The study was supported in part of a $6.2 million grant from the U.S. Army Research Office to investigate bacterial evolution, according to the school.