Nature Immunology: Strange DNA structure may lead to the development of cancer

Scientists at the LA JOLLA Institute of Immunology (LJI) have revealed how the lack of TET enzyme causes B-cell lymphoma

The new research was led by Dr.

This new research helps scientists finally link two dangerous phenomena in cancer cells

In previous studies, scientists discovered mutations that caused the loss of function of the TET enzyme in many blood cancer and solid cancer patients

In this project, scientists have explored a potential way in which TET defects are related to genome instability

"This research provides insights into an important issue in the field," Shukla said

Through the study of mouse lymphoma models, the researchers found that deleting TET2 and TET3 enzymes in mature B cells has a huge impact on B cell homeostasis

The team then performed genomic analysis to find clues about what was happening at the molecular level

DNA usually has two parallel strands, like the two railings of a ladder

Shulka and Samaniego-Castruita, with funding from the La Jolla Institute’s Tullie and Rickey Family Immunology Innovation Award, have studied these DNA structures in depth

When it comes to B-cell malignancies, the g-tetramer and the r-ring appear to be the missing link between exposing TET mutations and dangerous genomic instability

So, if the g-quadruplex and the r-ring cause problems, is there any way to prevent their formation?

Shukla and Samaniego-Castruita observed that DNMT1 was upregulated in tet-deficient B cells

Without TET enzyme, the normal exchange and absorption of DNA methylation markers is broken

In fact, the deletion of DNMT1 significantly delayed the development of aggressive b-cell lymphoma
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Samaniego-Castruita said that the deletion of DNMT1 was also related to a decrease in the levels of the g-four complex and r-ring
.

The researchers emphasized that regulating the g-tetramer and r-loop may be just one way for TET enzymes to control genome stability
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More work needs to be done to uncover the precise steps that cause tet-deficient cells to accumulate these mysterious structures in their DNA
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The team hopes to one day be able to devise a strategy through which the g-four complex and r-ring can be targeted to help cancer patients
.

As the Rao laboratory continues to study the role of TET enzymes, Shukla will join the Department of Cell and Developmental Biology at Northwestern University this winter
.
He plans to set up his own laboratory to focus on the study of different structural conformations in DNA
.

Article title

TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures