Accidental non-coding DNA
Let's talk about RNA splicing first. In molecular biology, this refers to the process of removing the introns and splicing the remaining exons together after the gene is transcribed into RNA. Only through correct RNA splicing can correct mRNA be formed. Previously, people found a protein called SF3B1 and found that it is the most mutated RNA splicing factor in cancer.
Due to the importance of SF3B1 in generating normal RNA, in the study, scientists recruited hundreds of patients with different cancers and looked for RNA mutations in their bodies. After analysis, they found that in patients with mutations in SF3B1, the RNA transcribed from the BRD9 gene was abnormal - in its sequence, a sequence from non-coding DNA appeared.
With an extra sequence, the protein product encoded by BRD9 will naturally not work properly. The researchers further discovered that BRD9 is an important tumor suppressor protein. Once it loses its function, it can lead to diseases such as uveal melanoma, chronic lymphocytic leukemia, and pancreatic cancer.
After finding the reason, the researchers used CRISPR technology to edit the BRD9 gene to prevent it from making mistakes in the process of RNA splicing. In addition, they also used antisense nucleotides to block the entry of non-coding DNA sequences. mRNA. These two methods have achieved good results, can inhibit the proliferation of mutant cells, and can also reduce the tumor volume in mice. Although this is still in the very early stage of development, it points to a potential treatment option.
"We know that many genetic mutations cause cancer. Mutations in SF3B1 are also strongly associated with many cancer types. But in the past, we didn’t know why SF3B1 mutations were so frequent or how to find a treatment,” said Professor Robert Bradley, one of the corresponding authors of this study: “Due to the breakthroughs in sequencing technology, computing power, and CRISPR genome engineering, we Discovered the cause of cancer caused by SF3B1, and also found a potential method to inhibit tumor progression. "
Carcinogenic mutations in "dark matter"
In two other studies, scientists have found cancer-causing mutations in the "dark matter" of the human genome. In this case, dark matter refers to the same "non-coding region" of DNA.
"Non-coding DNA is 98 percent of our genome. It doesn't code for proteins, so it's very difficult to study and is often overlooked, "said Professor Lincoln Stein, who led one of the studies." By carefully analyzing these regions, we found a single change in DNA letters that can drive many different types of cancer."
Specifically, the mutations found by the two teams appear in a type of small nucleic RNA called U1-SNRNA.Under normal circumstances, the function of U1-SNRNA is to recognize the 5 'splicing site by base pairing. After the mutation, the original A-U pairing will be mistakenly replaced by the C-G pairing, forming A new splicing product. Worse, because U1-SNRNA is involved in splicing a lot of RNA, it affects a lot of genes. Not only does it inactivate tumor suppressor genes, it also activates some oncogenes! Clinically, u1-SNRNA mutations are also strongly associated with liver cancer and chronic lymphocytic leukemia.
"These unexpected findings reveal new ways to target these cancers. You know, these cancers are very difficult to treat and have a high mortality rate. "Added Professor Michael Taylor, who led another study.
These three studies elucidate the important role of RNA splicing in the pathogenesis of cancer from two different perspectives. If the RNA splicing mechanism goes wrong, the number of genes downstream that might be affected is likely to be large. Similarly, if the problem of RNA splicing can be corrected at source, it may lead to novel cancer treatments. These studies tell us that when it comes to cancer, it's not enough to just focus on the coding region. Beyond the 2% of coding DNA sequences, there's 98% of the universe to explore.