a Loss of TET enzymes, which demethylate DNA, may lead to cancer. In TET-deficient mice, DNA forms strange structures called G-quadruplexes (G4s) and R loops that may lead to the development of cancer, according to a study conducted Dec. nature’s immunity It suggests.
The research paper “Great contribution to the field of G4/R ring biology,” Giovanni Capranico, a molecular biologist at the University of Bologna who was not involved in the study, wrote in an email to the scientist. “The major advance is the strong and convincing evidence that deletion of the TET gene causes B-cell metastasis, at least in mice, [which is] related with . . . G4s and R episodes,” he says. “An increase in non-canonical nucleic acid structures has already been observed in cancer cells, but this paper established a better-defined connection. ”
Anjana Rao, a cell and molecular biologist at the La Jolla Institute of Immunology, and her team described the role of TET proteins in mammalian DNA demethylation in 2009. Since then, Rao’s and other groups have found that TET proteins are involved in the regulation of gene expression, embryonic development and cancer. . Specifically, studies have linked TET deficiency to white blood cell cancer. So Rao and his colleagues wanted to know what happens when TET is absent from mature B cells.
To investigate this, the researchers used a targeted DNA-editing tool to create mice with genes for two of the three mammalian TET enzymes, Tet2 And Tet3And It is eliminated in mature B cells only (CD-19 positive). Mice with double TET knockout developed B-cell lymphoma within weeks, faster than mice infected with either. Tet2 or Tate 3 removed from their B cells. “It turns out it’s similar to this human disease called DLBCL [diffuse large B cell lymphoma]. DLBCL begins in the germinal centers, which is where T cells and B cells assemble together to form antibodies,” describes Rao. Stimulation of B cells that occurs there induces proliferation, but when B cells are stimulated with a double-knockout, they multiply rapidly, Rao adds. larger than normal B cells, giving rise to DLBCL-like carcinomas.
When the team focused at the molecular level, they discovered uncommon DNA structures called G-quadruplexes and R-loops. R-loops appear in DNA when RNA slips between the two DNA strands, while G-quadruplexes are “knots” in the DNA strands themselves. The DNA of mice lacking TET2 and TET3 formed these structures more frequently than mice with intact TET enzymes. G-quadruplexes and R-loops also impede replication forks, leading to transcriptional stress – a hallmark of cancer.
These G-quadruplex and R loops will lead to genome instability.
—Luisa Cimino, University of Miami
TET DNA demethylate enzymes, but its counterpart DNMT1 DNA methylates—and in TET-deficient B cells, where this balance was perturbed, DNMT1 was upregulated. When researchers deleted a file Dnmt1 Gene from mature B cells of TET knockout mice, DLBCL-like lymphoma developed later and mice survived longer. At the same time, quadruple G rings and R rings are becoming more and more rare. According to Rao, the B cells that eventually grew were those in which DNMT deletion failed while TET deletion succeeded.
This is “one of the first papers to definitely show how TET deficiency can cause genomic instability. These G-quadruplex and R loops will drive genome instability,” says Luisa Cimmino, a biochemist at the University of Miami who was not involved in the study, the scientist. “This is some of the first evidence to show this in a cancer model.”
Robert Hansel-Hirsch, a biochemist at the Center for Molecular Medicine in Cologne, Germany who was not involved in this study, says he similarly finds the relationship between TET and the formation of destabilizing DNA structures and homeostasis by removing the corresponding enzyme DNMT1 compelling and novel. He adds that the connection is particularly interesting because the enzymes’ activities (demethylation and methylation of cytosines)”[do] It has nothing to do with G-quadruplexes and R-rings directly. He notes that the mechanism behind how TET enzymes cause the structures to form remains unclear.
Cimmino suggests that the study “has enormous potential for any TET-deficient cancer”, but that it would have been more therapeutically relevant if a DNMT1 inhibitor had been used rather than a DNMT1 deletion. While Rao says she plans to focus on the basic outstanding research questions about TET’s shortcomings, she notes that first author Vipul Shukla, who recently started his own lab at Northwestern University, plans to investigate the idea further. If you apply DNMT1 inhibitors and G-quadruplex stabilizers together, can we cure cancer? Maybe we can,” she says.