Designing bridges in the genome

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Programming molecular bridges

In recent years, the CRISPR-Cas system has become nearly synonymous with genome editing. As it makes its way into human medicine, the search for new genome editing tools is more dynamic than ever, and a new system could enable us to insert, delete, or flip large segments of DNA.

Discovered in a family of transposable elements called IS110, the new system allows mobile DNA elements to jump from one location to another in the genome. The enzymes in this family use a unique RNA-based targeting system, called by the researchers bridge RNA. Picture this: the RNA has two loops—one end binds to the DNA that’s about to be inserted, while the other latches onto the target sequence in the genome, creating a molecular bridge.

By reprogramming the ends of this bridge RNA, the researchers managed to insert a piece of DNA almost 5000 bases long into E. Coli, and they used the system to excise and invert other pieces from the genome. Meanwhile, another research team characterized a similar family called IS111, using a similar mechanism that they called seek RNA.

This new system outshines CRISPR in three major ways:

• Size matters: CRISPR-based systems typically handle small rewrites to the genome, one or a few bases, while the new systems can manage thousands of bases.

• No breaks: CRISPR usually breaks the DNA and relies on the cell’s repair system, which can cause unintended damage. This new system skips the DNA-breaking step, avoiding potential genetic mishaps.

• Simplicity is key: While CRISPR often requires a complex mix of multiple proteins or fused enzymes for large genome edits, IS110 and IS1111 get the job done with a single, small protein.

However, before we get too excited, it's worth noting that these new systems currently don’t work in mammalian cells. However, researchers are already hard at work trying to solve the versatility problem, and I am sure that a mammalian version is not far.

Read more about the biochemistry and the structural biology of IS110, and read about IS111 here.

In other news:

• Freeze-dried mammoth: Scientist were able to assemble the genome a woolly mammoth that has been dead for 52 000 years, revealing similarities and differences with other elephants. And my DNA degrades if I look at it wrong. Read everything about it here.

• A leap for RNA synthesis: RNA oligonucleotides are emerging as powerful therapeutics, yet the traditional chemistry synthesis lags behind in the scale needed. Here, the researchers introduce a template-independent enzymatic process to synthetize RNA oligonucleotides.

• Lyophilized DNA origami: Tired of your DNA origami aggregating and stopping you from getting your best cryo-EM data? Then maybe try lyophilizing them. In this work, the team shows how the aggregation of structures can be greatly reduced by lyophilization!

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