12 October 2016

An enzyme could hold the key to new therapies for some types of non-Hodgkin’s lymphoma, new research has revealed.

Researchers in the USA and Canada found that uracil-DNA glycosylase (UNG) protects the ends of B cell chromosomes to help the growth of these antibody-producing cells in response to infection. 
The study, which is published in The Journal of Experimental Medicine, concludes that targeting this enzyme could be used to treat certain types of non-Hodgkin’s lymphoma.
When a B cell first encounters a foreign antigen, it proliferates and produces a DNA-modifying enzyme called activation-induced deaminase (AID). This enzyme goes on to create mutations in the cell’s immunoglobulin genes to produce a range of antibodies that can bind the antigen and mediate immune responses.
AID can also create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, it can lead to cancers.
In this study, led by Dr Ramiro Verdun, of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and Dr Javier Di Noia, of Institut de Recherches Cliniques de Montréal, looked to see if AID targets the telomeres of mouse B cells.
They found that when there is no UNG, AID created mutations in B cell telomeres that caused them to rapidly shorten, limiting the growth of activated B cells. UNG helped to repair these mutations, preventing telomere loss and facilitating B cell expansion.
Inhibiting UNG blocked the growth of human diffuse large B cell lymphoma cells expressing AID, the research found.
 “So UNG can contribute to lymphomagenesis by protecting telomeres from AID-induced damage,” said Dr Verdun. “We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers.”
Cortizas, E., et al. UNG protects B cells from AID-induced telomere loss. 2016. J. Exp. Med.
Link: http://dx.doi.org/10.1084/jem.20160635
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