Pseudogenes have long been considered to be genomic junk. A subclass of long noncoding RNA, these entities developed from the human genome’s 20,000 protein-coding genes but lost the ability to produce proteins. Yet the retention of these remnants throughout evolution suggests that they may have biological functions.
A research team at HMS and the Cancer Center at Beth Israel Deaconess Medical Center has provided some of the first evidence that one of these noncoding evolutionary relics has a role in causing cancer.
In a study published April 19 in Cell, the scientists report that, independent of any other mutations, abnormal amounts of the BRAF pseudogene led to the development of an aggressive lymphoma-like disease in a mouse model, a discovery suggesting that pseudogenes may play a primary role in a variety of diseases.
The discovery of this activity by pseudogenes also suggests that the functional genome could be three or four times its current known size.
“Our mouse model of the BRAF pseudogene developed cancer rapidly and aggressively,” says senior author Pier Paolo Pandolfi, the HMS George C. Reisman Professor of Medicine at Beth Israel Deaconess. “It’s remarkable that this very aggressive phenotype, resembling human diffuse large B-cell lymphoma, was driven by a piece of so-called junk RNA.”
The discovery hinges on the concept of competing endogenous RNAs (ceRNA), a functional capability for pseudogenes in which noncoding RNAs divert and sequester tiny pieces of RNA from their protein-coding counterparts so as to regulate gene expression.
The scientists wanted to determine whether this same ceRNA “cross talk” took place in a living organism with similar consequences.
The investigators focused on the BRAF pseudogene because it is known to exist in both humans and mice. The team created a mouse model in which the BRAF pseudogene was overexpressed and found that the mice overexpressing the pseudogene had higher levels of the BRAF protein and hyperactivation of a cancer-related pathway.
The investigators also found that the BRAF pseudogene is overexpressed in human B-cell lymphomas and that the genomic region containing the BRAF pseudogene is amplified in a variety of human cancers. Moreover, the authors say that silencing overexpressions of the BRAF pseudogene in human cancer cell lines led to reduced cell proliferation. This suggests that a therapy that reduces BRAF pseudogene levels may benefit cancer patients.
Photo: Nephron [creativecommons.org/licenses/by-sa/3.0] via Wikimedia Commons