Study reveals mechanism behind enzyme that tags unneeded DNA

February 18, 2016
A graphical representation of work investigating the mechanism of Suv39h1 using designer chromatin. Credit: Muir lab

Researchers have discovered the two-step process that activates an essential human enzyme, called Suv39h1, which is responsible for organizing large portions of the DNA found in every living cell.

For any particular cell, such as a skin or brain cell, much of this genetic information is extraneous and must be packed away to allow sufficient space and resources for more important genes. Failure to properly pack DNA jeopardizes the stability of chromosomes and can result in severe diseases. Suv39h1 is one of the main enzymes that chemically mark the irrelevant regions of DNA to be compacted by cellular machinery, but little is known about how it installs its tag.

Now, scientists at Princeton have used 'designer chromatin' templates - highly customized replicas of cellular DNA and histone proteins, the scaffolding proteins around which DNA is wrapped - to reveal new details about Suv39h1's mechanism. The researchers investigated how Suv39h1 employs a positive feedback loop to chemically tag thousands of adjacent histones, thus signaling the cell to stow away these underlying, unnecessary DNA sequences. The work was published in in the journal Nature Chemical Biology.

"One of the things that has always fascinated me about feedback loops is that they're super dangerous. If you make a mistake once, you end up getting reinforcement through the feedback loop," said Manuel Müller, a in the Muir lab and lead author on the study. "So how does Suv39h1 keep itself in check?"

Suv39h1 had been known to possess two distinct parts, but the new research revealed how they work together in order to 'switch on' the . One part of the enzyme, known as the chromodomain, is constantly exposed and seeks out specific chemical tags, known as a methyl groups, located at predetermined sites on histones. When the chromodomain finds these groups in the genome, it locks onto the spot and allows the other part, the enzymatic core, to install more methyl tags at adjacent histones.

"The second, anchoring step wasn't really known before. It provides an extra level of control and allows the process to be extremely fine-tuned," Müller said. A similar mechanism may be employed by many other enzymes operating on chromatin, given that they contain similar components of a .

To understand how the enzyme carries out this process, the researchers synthesized complex chromatin templates that were three times larger than previously reported models. They divided the template into three blocks that could each be manipulated in various ways. For example, a block could be prepared with the chemical tag present, absent or mutated such that tagging can't occur. "The different blocks should signal to the enzyme either start here or feel free to spread here or absolutely stop here," said Glen Liszczak, a co-author and postdoctoral researcher in the Muir lab.

By rearranging the various domains, the research team observed where the enzyme spread its mark across the genome. They found that Suv39h1 preferred to spread across small distances, but that it could reach sequences further along if chromatin folding decreased the physical distance in space.

"We've learned something new about this enzyme, something that we couldn't have without the pinpoint precision that the designer chromatin offers," Liszczak said. "There are a lot of questions that our lab has been interested in that we can now start to answer."

Explore further: Deficiency in p53 anti-tumor protein delays DNA repair after radiation

More information: Manuel M Müller et al. A two-state activation mechanism controls the histone methyltransferase Suv39h1, Nature Chemical Biology (2016). DOI: 10.1038/nchembio.2008

Related Stories

Enzyme controls transport of genomic building blocks

March 6, 2014

Our DNA and its architecture are duplicated every time our cells divide. Histone proteins are key building blocks of this architecture and contain crucial information that regulates our genes. Danish researchers show how ...

Recycling histones through transcription

March 26, 2015

Cells reuse a part of the histones which are used to pack DNA, according to a current study by Karolinska Institutet. The study, which is published in the journal Genome Research, was conducted on yeast cells, but it is likely ...

Discovered: How to unlock inaccessible genes

January 29, 2016

An international team of biologists has discovered how specialized enzymes remodel the extremely condensed genetic material in the nucleus of cells in order to control which genes can be used. The discovery will be published ...

Gene switch may repair DNA and prevent cancer

February 11, 2016

A team of scientists in Japan has found that a DNA modification called 5hmC – thought to be involved in turning genes on and off – localizes at sites of DNA damage and repair. They also found that a family of recently ...

Recommended for you

New method developed for producing some metals

August 25, 2016

The MIT researchers were trying to develop a new battery, but it didn't work out that way. Instead, thanks to an unexpected finding in their lab tests, what they discovered was a whole new way of producing the metal antimony—and ...

Electron microscopy reveals how vitamin A enters the cell

August 25, 2016

Using a new, lightning-fast camera paired with an electron microscope, Columbia University Medical Center (CUMC) scientists have captured images of one of the smallest proteins in our cells to be "seen" with a microscope.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.