Researchers have discovered that an enzyme called uracil DNA-glycosylase (Ung) protects the ends of B cell chromosomes to facilitate the proliferation of these antibody-producing cells in response to infection. This discovery further suggests that targeting Ung may help treat certain types of non-Hodgkins lymphoma. The study “Ung protects B cells from AID-induced telomere loss,” has been published in The Journal of Experimental Medicine.
When a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID). This enzyme creates mutations in the cell’s immunoglobulin genes so that the cell’s progeny produce a diverse repertoire of antibodies that can bind the antigen with high affinity and mediate various immune responses.
But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by Ung or other DNA repair proteins, this can lead to cancers such as non-Hodgkin’s lymphoma.
The new study by a team of researchers led by Ramiro Verdun of the University of Miami and Javier M. Di Noia of the Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute investigates whether AID targets the telomeres of mouse B cells. They chose this direction because telomeres—structures that protect the ends of chromosomes to facilitate cell proliferation—contain similar DNA sequences to immunoglobulin genes.
“The most interesting finding of this project was to observe that in the absence of Ung, AID caused mutations that led to DNA damage at the B cell telomeres. This damage caused the abrupt shortening of the telomeres, limiting the proliferation of B cells. Ung repaired these mutations, preventing telomere loss and facilitating B cell expansion.” said Dr. Di Noia
Ung’s ability to protect telomeres therefore helps B cells to continue proliferating while they mutate their immunoglobulin genes, allowing them to mount an effective immune response. But the enzyme’s activity may also help non-Hodgkin’s lymphoma cells, which often overexpress AID, to continue proliferating. The researchers found that inhibiting Ung blocked the growth of human diffuse large B cell lymphoma cells expressing AID.
“So Ung can contribute to lymphomagenesis by protecting telomeres from AID-induced damage,” says Dr. Verdun. “We show that cancerous human B cells expressing AID requires Ung for proliferation, suggesting that targeting Ung may be a means to delay the growth of AID-positive cancers.”
About the study
The research project was a close collaboration between the IRCM’s Mechanisms of Genetic Diversity research unit led by Dr. Javier Di Noia and the laboratory of Ramiro Verdun at the University of Miami. Astrid Zahn and Shiva Safavi from the IRCM shared first authorship with Dr. Verdun’s trainee Elena Cortizas.
The research in Dr. Di Noia’s laboratory was funded by the Canadian Institutes of Health Research and the Canada Research Chairs Program.
About the IRCM
Founded in 1967, the Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute is a non-profit organization that conducts fundamental and clinical biomedical research in addition to training high-level young scientists. With its cutting-edge technology facilities, the institute brings together 33 research teams, which work in cancer, immunology, neuroscience, cardiovascular and metabolic diseases, systems biology and medicinal chemistry. The IRCM also operates a research clinic specialized in hypertension, cholesterol, diabetes and cystic fibrosis, as well as a research centre on rare and genetic diseases in adults. The IRCM is affiliated with the Université de Montréal and associated with McGill University. Its clinic is affiliated with the Centre hospitalier de l’Université de Montréal (CHUM). The IRCM is supported by the Ministère de l’Économie, de la Science et de l’Innovation (Quebec ministry of Economy, Science and Innovation).
Source:
Manon Pepin
Executive Director, Communications and Public Relations | IRCM
514 987-5535 | manon.pepin@ircm.qc.ca
