A New Source for Mutations Found in Tumors

A study recently published in the Proceedings of the National Academy of Sciences furthers our understanding of tumors and the source of the mutations that are found within their DNA. This study, carried out by researchers at Wayne State University and Indiana University, highlights a new mutation signature found in cancer cells that is caused by members of the APOBEC3 family of proteins.

APOBEC3 enzymes are cytidine deaminases and known to catalyze the deamination of cytidine (C) to uridine (U) in single-stranded DNA substrates. These “errors” are usually corrected with the U getting converted back to a C; however, sometimes the U stays and gets converted to a thymidine (T), causing the unusual C-to-T mutation.

Using E. coli as their model organism, the researchers were able to show that, in the presence of a specific APOBEC3 enzyme, APOBEC3G (A3G), during DNA replication, C’s in the lagging strand template were converted to T’s three to four times more than in the leading strand template. Since the lagging strand is single-stranded for longer than the leading strand and due to the frequency with which the researchers saw the C-to-T mutation in the lagging strand, they hypothesized that A3G must be specifically targeting the lagging strand. Furthermore, since C-to-T mutations are the most frequently found mutations in tumor DNA, the researchers suggested that APOBEC3 enzymes are the source of these mutations, targeting the lagging strand DNA template during DNA replication in cancer cells. Their discovery could lead to new targets for preventing cancer and new treatments that specifically target the APOBEC3 enzymes.

Source: Wayne State University