Scientists at Northwestern Medicine, Chicago, Illinois, and La Jolla Institute for Immunology, California, discovered that the loss of TET enzymes is associated with B-cell lymphoma. These enzymes are vital for DNA demethylation and are important tumour suppressors. The scientists investigated a potential way in which the loss of TET enzyme function is connected to genomic instability, which is an increased likelihood for DNA mutations and other genetic changes to occur during cell division.
'Loss of TET function happens in cancer; genomic instability happens in cancer,' said Dr Vipul Shukla, assistant professor at Northwestern University. 'Genomic instability also happens in TET-deficient cells. What we found was that altered regulation of secondary DNA structures might be the reason for how these two events are related to one another.'
Published in Nature Immunology, the paper reports that deleting TET2 and TET3 enzymes in mature B-cells of mice resulted in the mice developing lymphoma, with an increased number of genomic instabilities, such as G-quadruplexes and R-loops, in their DNA.
G-quadruplexes are regions of four-stranded DNA in a knot-like conformation and R-loops are produced when a third rail, made of RNA, slips between two DNA strands and forces a gap between them. Both types of structure increase the fragility of the DNA.
Dr Shukla explained: 'They function as impediments in the DNA and if they don't resolve properly, they cause genomic instability... This study enlightened us that at least one of the reasons TET-deficient cells have more genomic instability might be due to the accumulation of these structures.'
DNMT1 is a regulatory enzyme that appears to change in response to TET levels, with increased levels in TET-deficient cells. The researchers determined that deleting the DNMT1 protein in TET-deficient B cells reduced the accumulation of G-quadruplexes and R-loops, and delayed B cell lymphoma development.
The researchers aim to further their research to see how drugs could stabilise these abnormal structures and be used as cancer treatment. 'The structures are like black boxes,' Dr Shukla commented, 'Because normally when you think about DNA, you think of a linear code with four letters. But this is asking you to think about not just the sequence itself, it's also the way DNA can fold into alternative conformations besides the double helix. This study sheds light on a new aspect of genome biology.'
Understanding how the loss of TET function leads to cancer development could reveal new drug strategies to target malignant cells. The team intends to further investigate how TET-deficient cells accumulate G-quadruplexes and R-loops, potentially devising methods to target these structures to treat multiple cancers.