Study suggests unknown gene key to antibody development

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Researchers at the University of Toronto have found that a neglected gene plays a major role in the development of antibodies, which help the immune system recognize and fight viruses, including SARS-CoV-2, bacteria and other causes of infectious diseases. The gene, FAM72A, facilitates the production of high-quality antibodies by enabling the effect of an enzyme called AID (for Activation-Induced Deaminase), the researchers showed. Immunologists have known for two decades that AID is essential for producing antibodies capable of clearing infections, but the full mechanism of its effect has remained unknown. The journal Nature published the results, back to back with similar results from a research group in France.

“Our results answer the long-standing question of how AID does its job,” said Alberto Martin, professor of immunology at the Temerty School of Medicine at the University of Toronto. “FAM72A helps AID promote mutations in antibody genes which are essential for the development of effective antibodies.” Genetic mutations that lead to long-lasting changes in DNA occur through a process called mutagenesis. In the context of antibody development, mutagenesis takes place largely through AID-driven mechanisms called somatic hypermutation and class-switching recombination – which help antibodies acquire the diversity and potency they have. need to counter a wide range of pathogens.

The results from the Martin lab should help researchers better understand the development of antibodies in the broad sense, but they also have implications for cancer. Uncontrolled mutagenesis in B cells that produce antibodies is linked to B cell lymphoma, and FAM72A is present at very high levels in other cancers such as gastrointestinal, breast, lung, liver and other cancers. ovaries. “Our data show that high levels of FAM72A promote mutations in antibody genes, so increased levels of FAM72A could stimulate cancer development, progression or drug resistance by increasing mutagenesis,” explains Martin.

Martin’s team is now exploring these possibilities. Oddly enough, unlike other mammals, humans have four versions of FAM72A genes and their roles in cancer and antibody production are still unknown. Yuqing Feng, postdoctoral fellow at Martin’s lab, first identified FAM72A as a gene of interest through genetic screening. She produced the screen with technology designed by Jason Moffat, professor in the Department of Molecular Genetics at the University of Toronto and at the Donnelly Center for Cellular and Biomolecular Research.

“The platform is a very powerful tool for discovering new genes, and Jason’s group provided invaluable advice on the design and execution of the screen,” said Feng. The platform generated a short list of genes with mostly known functions that may play a role in B cell mutagenesis, but Feng says she was more interested in the poorly characterized genes on the list.

The FAM72A stood out in part because so little was known about its biology. “I had read an article from 2008 which suggested that FAM72A binds to UNG2, but with no apparent functional consequences. It was interesting because we knew that UNG2 was important in the pathways we were studying,” says Feng.

This connection turned out to be a great lead. Feng was able to show in experiments with B cells that FAM72A binds to and causes the destruction of UNG2, thus allowing mutagenesis. Conglei Li, another Martin Lab postdoctoral fellow, reproduced these results in mice. “We generated FAM72A-deficient knockout mice and observed that they exhibited a compromised antibody response,” said Li, who will be launching his own lab at the Chinese University of Hong Kong next month.

Li also showed that when UNG2 is overactive, it can interfere with the beneficial effect of AID. Li says he’s grateful the lab was able to continue working together throughout the COVID-19 pandemic – when most research at the university has had to stop.

Feng supports this sentiment. “Our team overcame so many difficulties to continue this work during the pandemic, from reducing animal colonies to self-isolation, then limited lab hours and shift work,” Feng said. “We are really passionate about our work, and by working together we haven’t let Covid stop us.” (ANI)

(This story was not edited by Devdiscourse staff and is auto-generated from a syndicated feed.)


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