How to Tame a Restless Genome

Short bits of DNA – hopper genes – can bounce from place to place in our genomes. When a lot of DNA fragments move, cancer, infertility, and other problems can arise. Cold Spring Harbor Laboratory (CSHL) professor, HHMI investigator Lemur Joshua Thor and a research researcher in her lab, Jonathan Ipsaro, study how cells protect the integrity of the genome and freeze these disturbed portions of DNA. And they found that one of the most needed jumping gene resources may also be its greatest weakness.

The mammalian genome is full of genetic elements that have the ability to move from one place to another. One type is LTR retrotransposon (LTR). In normal cells, these elements do not move around much. But if something happens that allows them to move, for example during sexual reproduction or in cancer cells, Joshua Thor says:

“Sometimes they jump to very important points, either the genes themselves or the genome regions that are important for gene regulation.”

In this study, Joshua-Tor and Ipsaro examined a mouse protein called Asterix / Gtsf1 that immobilizes LTRs. To understand how this protein turns off LTRs, Ipsaro used several techniques, including cryo-EM, to get a closer look at the protein’s structure. Joshua Tor says:

“The structure teaches us in a number of ways, such as how to do things. If you can see something, you have a better idea of ​​how it works.”

Ipsaro found that Asterix / Gtsf1 directly binds to a specific class of RNA called transport RNA (RNA). RNA is usually part of the protein synthesis mechanism in the cell. LTRs borrowed this part of the protein-making machinery to duplicate their genetic material. Asterix / Gtsf1 goes beyond what LTRs are trying to do by immobilizing the moving element in place and stopping their mobility. Ibsaro says:

It’s trying to copy and paste itself throughout the genome. And part of it evolutionarily relied on RNA binding for replication. ”

Instead of freezing the entire genome, scientists believe Asterix / Gtf1 uses tRNA to suppress small specific regions, such as LTRs. Researchers are trying to figure out how cells protect themselves from these and other mobile genetic elements. They hope to someday be able to tame a highly disturbed genome, and prevent new mutations in the germline and tumors.


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