This is a graphical representation of work investigating the mechanism of Suv39h1 using designer chromatin. Credit: Image provided by the Muir lab
Essential DNA packing enzyme relies on 2-step activation to ensure correct genetic organization. For any particular cell, eg 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.
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. “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. “So how does Suv39h1 keep itself in check?”
Suv39h1 has 2 distinct parts, but new research revealed how they work together to ‘switch on’ the enzyme. A part of the enzyme, the chromodomain, is constantly exposed and seeks out methyl groups, located at predetermined sites on histones. It locks onto the spot and allows 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 other enzymes operating on chromatin, as they have similar components of a feedback loop.
To understand how the enzyme carries out this process, they synthesized complex chromatin templates 3X larger than previously reported models. They divided the template into 3 blocks that could each be manipulated in various ways. Eg, 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.
By rearranging the various domains, they observed where the enzyme spread its mark across the genome. Suv39h1 preferred to spread across small distances, but that it could reach sequences further along if chromatin folding decreased the physical distance in space. http://chemistry.princeton.edu/news/study-reveals-mechanism-behind-enzyme-tags-unneeded-dna
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