Pseudogenes are commonly labeled as “junk DNA” given their perceived nonfunctional status. However, the advent of large-scale genomics projects prompted a revisit of pseudogene biology, highlighting their key functional and regulatory roles in numerous diseases, including cancers.
Integrative analyses of cancer data have shown that pseudogenes can be transcribed and even translated, and that pseudogenic DNA, RNA, and proteins can interfere with the activity and function of key protein coding genes, acting as regulators of oncogenes and tumor suppressors.
Rochester biologists show how selfish genetic elements that can cause tumors may also trigger the death of cancer cells.
Selfish genetic elements were once thought to be merely parasites of the genome. But researchers at the University of Rochester have discovered that this so-called “junk DNA” may actually be key to preventing tumors.
The researchers, including Vera Gorbunova, the Doris Johns Cherry professor of biology; Andrei Seluanov, professor of biology; and Yang Zhao, a former postdoctoral research associate in Gorbunova’s lab, report in a paper in Nature Immunology that blind mole rats use selfish genetic elements called retrotransposons to shield themselves from cancer.
“Retrotransposable elements were traditionally viewed as mutagens that impose cancer risks and advance aging,” says Zhao, the lead author of the paper. “Our new study suggests, however, that retrotransposable elements can actually suppress tumors.”
The human genome is littered with selfish genetic elements – repetitive elements that do not seem to benefit their hosts but instead seek only to propagate themselves by inserting new copies into their host genomes.
Retrotransposons are the most prevalent selfish genetic elements found in humans; approximately 45 percent of the human genome is made of retrotransposons.
As reported in their most recent paper, however, Gorbunova, Seluanov, and Zhao found that retrotransposons are a double-edged sword: if left unchecked, they can wreak havoc in a genome. But they may also trigger mechanisms that kill rapidly proliferating cells – the type of cells that lead to tumors.
“For decades, people had focused on the bad side of retrotransposons as inducing tumors, since transposon activity is often higher in tumors,” Gorbunova says. “We show that this elevated transposon activity is actually what the organism leverages to identify and kill the cancerous cells.”
The key is to maintain a balance between activating and suppressing the retrotransposons, which Gorbunova likens to training a guard dog: you want to train a guard dog to alert you and defend against intruders, but you also don’t want the dog to blindly bite every person with whom it comes in contact.
A research team headed by Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, recently identified a DNA region known as VNTR2-1 that appears to drive the activity of the telomerase gene, which has been shown to prevent aging in certain types of cells, including reproductive cells and cancer cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Knowing how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.
Junk no more
Zhu said that his team’s latest finding that VNTR2-1 helps to drive the activity of the telomerase gene is especially notable because of the type of DNA sequence it represents.
“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” Zhu said. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matters in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”
Their finding is based on a series of experiments that found that deleting the DNA sequence from cancer cells – both in a human cell line and in mice – caused telomeres to shorten, cells to age, and tumors to stop growing. Subsequently, they conducted a study that looked at the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008.
The researchers found that the length of the sequence ranged from as short as 53 repeats – or copies – of the DNA to as long as 160 repeats.
“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Zhu said.
Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants.
However, Zhu said it was worth noting that having a shorter sequence does not necessarily mean your lifespan will be shorter, because it means the telomerase gene is less active and your telomere length may be shorter, which could make you less likely to develop cancer.
“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Zhu said. “We know that oncogenes—or cancer genes—and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”
Blind mole rats offer special insights
Gorbunova and Seluanov have long studied longevity and disease resistance in exceptionally long-lived animals. They focus on rodents because they are genetically similar to humans and have a diverse range of lifespans. Understanding why certain rodents are cancer-resistant offers scientists clues to uncover anticancer mechanisms that may be applicable to humans.
One such rodent is the blind mole rat, a small species that spends its entire life in underground burrows. Blind mole rats have exceptionally long lifespans for rodents their size; they can live up to 21 years, which is nearly five times that of similar size rodents like mice. Their longevity is often attributed to their remarkable resistance to cancer and other age-related diseases.
Gorbunova and Seluanov previously discovered that blind mole rats prevent cancer by activating “concerted cell death,” but the mechanisms at play were a mystery.
Now, the researchers believe retrotransposons may be one key piece to the puzzle. Why? Because they discovered that blind mole rats have evolved to leverage retrotransposons to their advantage to kill cancer cells.
The rodents naturally express low levels of an enzyme called DNA-methyltransferase 1 (DNMT1). After cells divide, DNMT1 modifies each new DNA strand to control gene expression, including silencing retrotransposons. If cells replicate too fast, as is the case with cancerous cells, having a low level of DNMT1 means the DNMT1 can’t keep up and retrotransposons are more active. In the case of the blind mole rat, this can be a good thing: the retrotransposons then mimic a viral infection by accumulating in the cells’ cytoplasm, which triggers an immune response to kill the cells that are reproducing at a rapid pace.
Leveraging the power of retrotransposons in human cells
Initially, the researchers believed the mechanisms behind leveraging retrotransposons were unique to blind mole rats. However, they found the same mechanisms at work in human tissue cells. When they either lowered the level of human DNMT1 or boosted the activation of retrotransposons, they were able to kill cells proliferating at rapid speeds.
The researchers still need to figure out exactly how blind mole rats have achieved the balance between activating and suppressing retrotransposons. For now, though, they will focus on the power of selfish genetic elements to be, well, not so selfish.
“Even though humans haven’t evolved to leverage transposons quite like blind mole rats, our paper shows that similar mechanisms do exist in humans,” Gorbunova says. “We can use this information to inhibit cancer cell growth by developing more selective treatments that enhance cell machinery and processes that already exist.”
More information: Yang Zhao et al, Transposon-triggered innate immune response confers cancer resistance to the blind mole rat, Nature Immunology (2021). DOI: 10.1038/s41590-021-01027-8