Researchers identify new role for tRNA fragments in tumour suppression.


For years, scientists have been puzzled by the presence of short stretches of genetic material floating inside a variety of cells, ranging from bacteria to mammals, including humans. These fragments are pieces of the genetic instructions cells use to make proteins, but are too short a length to serve their usual purpose. Now, researchers at the Rockefeller University have discovered a major clue to the role these fragments play in the body, and in the process, may have opened up a new frontier in the fight against breast cancer.  The opensource study is published in the journal Cell.

Specifically, the team discovered that these particular genetic fragments of a type of RNA known as transfer RNA (or tRNA), appear to be capable of reducing the growth and spread of breast cancer cells.  The team state that this is a new basic mechanism the body uses to control the growth of cancer.  They now plan to explore it further to open up new ways of curbing cancer that have never been tried before and to reveal new basic insights on how genes are regulated inside human cells.

Previous studies have found tRNA fragments in all walks of life, and that they consistently increase in number when cells are exposed to low oxygen levels and other forms of cellular stress. But their purpose in the body has remained mysterious  What those fragments are there for, and their role, is poorly defined.

The current study discovered that breast cancer cells generate tRNA fragments when exposed to low levels of oxygen. And cancer cells that carry more of these particular genetic fragments are less likely to metastasize. What’s more, adding these fragments to cells reduced the growth and progression of cancer; blocking the fragments, in turn, led to the opposite effect.

Looking closer, the researchers saw that tRNA fragments that come from specific tRNAs (glutamic acid, aspartic acid, glycine, tyrosine) bind to a key player in the life cycle of a cancer cell. This key player, known as an oncogene, normally binds to other RNAs and increases their numbers, causing them to make more of the oncogenes that help cancer cells divide and spread.  These tRNA fragments bind to the oncogene, called YBX1, and push out the other RNAs that encode for oncogenes, reducing cancer cells’ ability to grow and metastasize. By doing so, they represent a new class of molecules in the cell called tumour suppressors.

The team state that these tRNA fragments are demonstrating an entirely novel way of regulating gene expression. By blocking YBX1’s ability to bind other RNAs whose expression YBX1 increases, tRNA fragments are playing a part in how the body expresses genes.

The data findings back up the premise that the number of tRNA fragments would increase in periods of cellular stress, such as when the cell is exposed to low oxygen levels  The team explain that cells can sense whether they don’t have sufficient energetic currency that occurs during low oxygen states, and tRNA fragments help suppress cells’ growth rate so they can preserve their energy and nutrients for when the stress resolves.

The researchers stress that of course, aggressive breast cancer cells often find ways to sidestep the body’s efforts to control them, including those involving these tRNA fragments.  The team state they are very interested in figuring out how aggressive breast cancer cells stop the production of tRNA fragments.  The team surmise that these tRNA fragments are revealing a completely new way by which expression of oncogenes is regulated as a means of controlling cancer growth.

Source:  The Rockefeller University

 

Upon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs), yielding distinct classes of tRFs. We identify a novel class of tRFs derived from tRNAGlu, tRNAAsp, tRNAGly, and tRNATyr that, upon induction, suppress the stability of multiple oncogenic transcripts in breast cancer cells by displacing their 3′ untranslated regions (UTRs) from the RNA-binding protein YBX1. This mode of post-transcriptional silencing is sequence specific, as these fragments all share a common motif that matches the YBX1 recognition sequence. Loss-of-function and gain-of-function studies, using anti-sense locked-nucleic acids (LNAs) and synthetic RNA mimetics, respectively, revealed that these fragments suppress growth under serum-starvation, cancer cell invasion, and metastasis by breast cancer cells. Highly metastatic cells evade this tumor-suppressive pathway by attenuating the induction of these tRFs. Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action. This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments.  Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement.   Tavazoie et al 2015.

Upon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs), yielding distinct classes of tRFs. We identify a novel class of tRFs derived from tRNAGlu, tRNAAsp, tRNAGly, and tRNATyr that, upon induction, suppress the stability of multiple oncogenic transcripts in breast cancer cells by displacing their 3′ untranslated regions (UTRs) from the RNA-binding protein YBX1. This mode of post-transcriptional silencing is sequence specific, as these fragments all share a common motif that matches the YBX1 recognition sequence. Loss-of-function and gain-of-function studies, using anti-sense locked-nucleic acids (LNAs) and synthetic RNA mimetics, respectively, revealed that these fragments suppress growth under serum-starvation, cancer cell invasion, and metastasis by breast cancer cells. Highly metastatic cells evade this tumor-suppressive pathway by attenuating the induction of these tRFs. Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action. This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments. Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement. Tavazoie et al 2015.

 

 

 

 

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