DNA, or deoxyribonucleic acid, is a molecule that contains the genetic instructions for everyday cell life. DNA can be damaged by radiation, chemicals, cancer drugs and other environmental stresses, and errors can also arise when DNA is copied before a cell divides, a process called replication. Cells correct many of these errors through several repair systems, such as mismatch repair (MMR). Unfortunately, mutations in genes involved in DNA MMR can lead to an increased risk of certain cancers, such as Lynch syndrome-associated colorectal cancer. Numerous enzymes are involved in DNA repair, including three prime repair exonuclease 2 (TREX2), which helps cells keep copying their DNA when they run into damage. Understanding what TREX2 does helps explain how mutations arise in cells.

Research led by Professor Paul Hasty from the University of Texas Health San Antonio and a team including Dr. Teresa Marple, Dr. Mi Young Son, Dr. Jun Ho Ko, Dr. Xiaodong Cheng, and Professor Patrick Sung, examined how TREX2 contributes to DNA mutations, both without treatment and after exposure to DNA-damaging agents. The study, published in Cell Reports, found that TREX2 is responsible for most of the spontaneous mutations in lab-grown mouse embryonic stem cells and human cancer cells that lack mismatch repair.

The team deleted all of the TREX2 gene’s coding sequences in mouse embryonic stem cells. They then exposed cells with and without TREX2 to ten DNA-damaging agents, including the cancer drug cisplatin and ionizing radiation, plus a drug that slows gene activity. Even without treatment, cells lacking TREX2 had significantly fewer mutations than normal cells. Every treatment raised mutations in both types of cells, but levels stayed lower in cells without TREX2. Professor Hasty explains, “These data support the premise that TREX2 is responsible for converting a variety of DNA lesions into genetic mutations spontaneously and upon treatment with a genotoxin.”

Further, Professor Hasty and his research group compared mouse cells with and without MSH2, a protein needed for mismatch repair. Without mismatch repair, mutations rose sharply, but removing TREX2 cut them by roughly 100-fold or more in one test and brought them back to about normal levels in another. Lowering TREX2 also reduced mutations in three lab-grown human cancer cell lines, from colorectal, ovarian and blood cancers. Cells missing both MSH2 and TREX2 showed a different problem: when treated with drugs that block DNA copying, they were more sensitive and their DNA copying stalled more often, while they showed fewer DNA breaks after treatment with another cancer drug.

After analyzing all the data, Professor Hasty speculated about the possible interactions between TREX2 and MMR. He explains, “MMR suppresses mutations that are caused by mismatches and base lesions, while TREX2 generates mutations that are largely repaired by MMR or caused by MMR deficiency.” The researchers note that their study used only two types of mutation test and looked at only two of the cell’s systems for handling copying errors, and that large-scale DNA sequencing might be better suited to future work.

This study by Professor Hasty and his team paves the way for further research on how enzymes that handle damaged DNA can also create mutations. Because faulty mismatch repair underlies Lynch syndrome, learning how TREX2 creates mutations in such cells may help researchers understand how these cancers develop, although the work so far has been done only in cells grown in the lab.

Journal Reference

Teresa Marple, Mi Young Son, Xiaodong Cheng, Jun Ho Ko, Patrick Sung, Paul Hasty. TREX2 deficiency suppresses spontaneous and genotoxin-associated mutagenesis. Cell Reports, 2024, 43(1), 113637. DOI: https://doi.org/10.1016/j.celrep.2023.113637