03:26pm Wednesday 13 December 2017

Two Kinds of Enzymes Work Together to Stamp DNA with "Turned Off" Signal

News Article ImageThis coordination makes sure that the cell sees multiple signals saying the same thing: that the gene in question is on or off.

In cells, methylation can be found both on the DNA (blue string) and the histones (golden spools ). Having both kinds of methylation provides two signals to the cell that the gene in question should be turned off.

The results were published Tuesday, Nov. 15 by the journal Nature Communications.

Inside the cell nucleus, DNA is wound around spool-like proteins called histones, which carry a variety of chemical modifications that depend on whether the DNA is active or shut off. One of these modifications is methylation, attachment of the methyl chemical group (CH3-) in a specific place.

Researchers led by Xiaodong Cheng, PhD, professor of biochemistry, have shown that Dnmt3a, an enzyme that adds methyl groups to DNA, works hand in hand with GLP, an enzyme that adds methyl groups to histones at the specific site of histone H3 lysine 9. Cheng is a Georgia Research Alliance Eminent Scholar.

The first author is postdoctoral fellow Yanqi Chang. Collaborators at the H. Lee Moffitt Cancer Center, M.D. Anderson Cancer Center and Kyoto University contributed to the paper.

“We found Dnmt3a is actually methylated by GLP,” Cheng says. “This modification also allows a third protein, called MPP8, to fasten Dnmt3a and GLP together. This is a molecular explanation for why DNA methylation and H3K9 methylation tend to appear together.”

Chang and co-workers used X-ray crystallography at the Argonne National Laboratory’s Advanced Photon Source and biochemical assays to examine how GLP acts on Dnmt3a and how MPP8 recognizes the other two proteins.

MPP8 fastens the two methylating enzymes together.

Both DNA methylation and H3K9 methylation are generally found on genes that are turned off. In contrast, methylation at other histone sites can be found on active genes. Changes in methylation patterns – on genes that suppress growth — underpin a healthy cell’s transformation into a cancer cell, for example.

Methylation is part of an “epigenetic code”: the information provided by the chemical modifications on the DNA, histones and the proteins surrounding the DNA, separate from the information in the DNA sequence itself.

“These protein interactions are what makes the epigenetic code consistent. Yet very little is known about the methylation of non-histone proteins,” Cheng says. “I think that many proteins will turn out to be potential substrates for enzymes that add methyl groups to proteins.”

One example was a finding by Cheng, Winship Cancer Institute researcher Paula Vertino and colleagues in 2008. They found that methylation affects the durability of the estrogen receptor, an important molecule in breast cancer cells (and healthy cells too).

The research was supported by the National Institutes of Health.

Reference:  Y. Chang et al. MPP8 mediates the interacts between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat. Commun. (2011).
Doi: 10.1038/ncomms1549  

Writer: Quinn Eastman

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